Novel serine protease genes related to DPPIV

ABSTRACT

Novel proteins or polypeptides having significant sequence homology to DPPIV, nucleic acids coding therefor, cells which have been modified with such nucleic acid so as to express these proteins, antibodies to these proteins, screening methods for the discovery of new therapeutic agents which are inhibitors of the activity of these proteins or of related proteins, and therapeutic agents discovered by such screening methods, as well as new therapeutic treatments, are all provided.

[0001] This application claims priority from U.S. provisionalapplication Serial No. 60/240,117, filed Oct. 12, 2000, the disclosureof which application is expressly incorporated by reference.

FIELD OF THE INVENTION

[0002] The present invention relates to novel serine proteases relatedto dipeptidyl peptidase IV (DPPIV), and to isolated nucleic acids codingfor these proteases, all of which are useful for the discovery of newtherapeutic agents, for measuring protease activity, and for determiningthe inhibitory activity of compounds against these proteases.

BACKGROUND OF THE INVENTION

[0003] Proteases and peptidases are enzymes that catalyse the hydrolysisof peptidic amide bonds. Proteases play an important role in theregulation of biological processes in almost every life-form frombacteria to virus to mammals. They perform critical functions in, forexample, digestion, blood clotting, apoptosis, activation of immuneresponses, zymogen activation, viral maturation, protein secretion andprotein trafficking. They can be classified according to a number ofcriteria, such as site of action, substrate preference, and mechanism.So, for example, aminopeptidases act preferentially at the N-terminalresidues of a peptide, while carboxypeptidases act preferentially at theC-terminus and endopeptidases act at sites removed from the two termini.Among the carboxy- and aminopeptidases, peptidyl peptidases cleave asingle amino acid residue from the substrate, dipeptidyl peptidasescleave a dipeptide unit (two amino acids) from the substrate, andtripeptidases cleave three amino acids from the substrate. Substratepreference is frequently expressed in terms of the amino acid residueimmediately N-terminal to the cleavage site. For example, trypsin-likepeptidases will preferentially cleave a peptide next to a basic aminoacid (arginine or lysine), i.e. where the bond hydrolysed is theArg/Lys-Xaa bond. As another example, the chymotrypsin-like family ofpeptidases preferentially hydrolyse peptides adjacent to an aromaticresidue. Mechanistically, peptidases are classified as beingserine-dependent, cysteine-dependent, aspartic acid-dependent orzinc-dependent.

[0004] Because peptidases and proteases are involved in the regulationof many physiological processes, they are attractive targets for thedevelopment of therapeutic agents. Protease and peptidase inhibitorsare, for example, used in the treatment of hypertension, coagulationdisorders, and viral infection.

[0005] Proteolytic enzymes that exploit serine in their catalyticactivity are ubiquitous, being found in viruses, bacteria andeukaryotes. Over 20 families (denoted S1- S27) of serine protease havebeen identified; these are grouped into 6 clans (SA, SB, SC, SE, SF andSG) on the basis of structural similarity and other functional evidence.Structures are known for four of the clans (SA, SB, SC and SE); theseappear to be totally unrelated, suggesting at least four evolutionaryorigins of serine peptidases and possibly many more, Rawlings andBarrett, Meth. Enzymol. 244: 19-61 (1994).

[0006] The prolyl oligopeptidase family consists of a number ofevolutionarily related peptidases whose catalytic activity seems to beprovided by a charge relay system similar to that of the trypsin familyof serine proteases, but which evolved by independent convergentevolution. A conserved serine residue has been shown experimentally (inE. coli protease II as well as in pig and bacterial PE) to be necessaryfor the catalytic mechanism. This serine, which is part of the catalytictriad (Ser, His, Asp), is generally located about 150 residues away fromthe C-terminal extremity of these enzymes (which are all proteins thatcontains about 700 to 800 amino acids).

[0007] One of the most intensively studied prolyl oligopeptidases isdipeptidyl peptidase IV (DPPIV, EC 3.414.5), a type II glycoprotein,which is the only well characterised dipeptidyl aminopeptidase known tobe located on the outer side of plasma membranes. As indicated above,dipeptidyl aminopeptidases are characterised by their ability to cleaveN-terminal dipeptides from a variety of small peptides. Dipeptidylaminopeptidases show different substrate specificities and cellularlocalisation, suggesting different functions of each activity in peptideprocessing. DPPIV is characterised by its capacity to cleave N-terminaldipeptides containing proline or alanine as the penultimate residue. TheDPPIV gene spans approximately 70 kb and contains 26 exons, ranging insize from 45 bp to 1.4 kb. The nucleotide sequence (3,465 bp) of thecDNA contains an open reading frame encoding a polypeptide comprising766 amino acids. The nucleotides that encode the active site sequence(G-W-S-Y-G) are split between 2 exons. This clearly distinguishes thegenomic organisation of the prolyl oligopeptidase family from that ofthe classic serine protease family.

[0008] DPPIV is widely distributed in mammalian tissues and is found ingreat abundance in the kidney, intestinal epithelium and placenta(Yaron, A. and Naider, F., Critical Reviews in Biochem. Mol. Biol. 1993[1], 31). In the human immune system, the enzyme is expressed almostexclusively by activated T-lymphocytes of the CD4⁺ type where the enzymehas been shown to be synonymous with the cell-surface antigen CD26.Although the exact role of DP-IV in human physiology is still notcompletely understood, recent research has shown that the enzyme clearlyhas a major role in human physiology and pathophysiology.

[0009] On human T cells, DPPIV expression appears late in thymicdifferentiation and is preferentially restricted to the CD4⁺helper/memory population, and CD26 can deliver a potent co-stimulatoryT-cell activation signal. DPPIV, also known as T-cell activation antigenCD26, therefore plays an important role in the immune response viaassociation with CD45 tyrosine phosphatase and, through its ability tobind adenosine deaminase (ADA) to the T-cell surface, protects theT-cell from adenosine-mediated inhibition of proliferation. Furthermore,the regulation of the function of chemokines by CD26/DPPIV appears to beessential for lymphocyte trafficking and infectivity of HIV strains.DPPIV has been associated with numerous functions including involvementin T-cell activation, cell adhesion, digestion of proline containingpeptides in the kidney and intestines, HIV infection and apoptosis, andregulation of tumorigenicity in certain melanoma cells, Pethiyagoda etal., Clin. Exp. Metastasis 2000;18(5):391-400. DPPIV is also implicatedin the endocrine regulation and metabolic physiology. More particularly,DPPIV cleaves the amino-terminal His-Ala dipeptide of GLP-1, generatinga GLP-1 receptor antagonist, and thereby shortens the physiologicalresponse to GLP-1. Glucagon-like peptide-1 (GLP-1), an incretin thatinduces glucose-dependent insulin secretion, is rapidly degraded byDPPIV, and since the half-life for DPPIV cleavage is much shorter thanthe half-life for removal of GLP-1 from circulation, a significantincrease in GLP-1 bioactivity (5- to 10- fold) is anticipated fromDPP-IV inhibition. Inhibitors of DPPIV are currently being studied inthe clinic as potential therapeutic agents for type 2 diabetes andimpaired glucose tolerance.

[0010] Various different inhibitors of DPPIV were known in 1993. One ofthese is a suicide inhibitor N-Ala-Pro-O-(nitrobenzoyl-) hydroxylamine.Another is a competitive inhibitor: e-(4-nitro) benzoxycarbonyl-Lys-Pro,and another is a polyclonal rabbit anti-porcine kidney DPPIVimmunoglobulin. Others have since been developed and are described indetail in U.S. Pat. Nos. 5,939,560, 6,110,949m 6,011,155 and 5,462,928.

[0011] In addition to, but independent of, its serine type catalyticactivity, DPPIV binds closely to the soluble extracellular enzymeadenosine deaminase (ADA), acting as a receptor and is thought tomediate signal transduction. DPPIV structure is characterized by twoextracellular domains, an α/62 fold hydrolase domain and a 7-bladebeta-propeller domain consisting of repeated beta sheets of about 50amino acids. Recently it has been shown that, besides selectingsubstrates by size, the beta-propeller domain, containing 10 of the 12highly conserved cysteine residues, contributes to catalysis of thepeptidase domain. In addition, the cysteine-rich domain is responsiblefor DPPIV-binding to collagen I and to extracellular ADA. DPPIV is alsoreported to play a role in fibronectin-mediated interactions of cellswith extracellular matrix. Recent studies show that the proteaseactivity of DPPIV is not required for its anti-invasive activity becausemutants of DPPIV that lack the extracellular serine protease activitymaintain such activity.

[0012] A number of proteins that share similarities with DPPIV have beenreported in the literature. Several of these proteins have been clonedincluding DPP-I, DPP-II, DPP-III, DPP-X and fibroblast activationprotein (FAP). These have been identified and characterised either bymolecular cloning and functional studies of expressed proteins or asbiochemical activities in tissue extracts. DPPIV-beta and other novelpeptidases with functional similarities to DPPIV are not yet cloned. Theidentification, characterization and/or appropriate classification offurther members of the family of prolyl oligopeptidases, the elucidationof their physiological (and particularly pathophysiological) role, andthe application of that knowledge to the development of new therapeuticagents are significant challenges.

SUMMARY OF THE INVENTION

[0013] The present invention provides proteins with prolyloligopeptidase(post-proline cleaving) activities that constitute three novel membersof a family of proteins related to DPPIV, including the full-lengthproteins, alternative splice forms, subunits, and mutants, as well asnucleotide sequences encoding the same. The present invention alsoprovides methods of screening for substrates, interacting proteins,agonists, antagonists or inhibitors of the above proteins, andfurthermore to pharmaceutical compositions comprising the proteinsand/or mutants, derivatives and/or analogues thereof and/or ligandsthereto.

[0014] These novel proteins having significant sequence homology toDPPIV are termed dipeptidyl peptidase IV-related protein-1, 2 & 3(DPRP-1, DPRP-2 and DPRP-3). The amino acid sequences of DPRP-1, DPRP-2and DPRP-3 are given in SEQ. ID NOS: 1, 3 and 5 respectively. Furtherdisclosed are nucleic acid sequences coding for these proteins (SEQ. IDNOS: 2, 4 and 6). Table 1 illustrates the homology (i.e. similarity)between the novel proteins DPRP-1, DPRP-2 and DPRP-3 and other knownserine proteases. TABLE 1 Comparison of the sequences of these threenovel proteins with DPPIV and other Clan SC, Family S9 members andSubfamily B members Protease Protease Homology TM Ser-Asp-His Familyname No. of a.a. with DPPIV region Triad Gene location Optimal pH ClanCA, DPPI 463 N N N 11q14.1-q14.3 — Family C1 Clan SC, DPPII 500 N Y N —4.5-6.0 Family S28 QPP 492 N N N — 4.5-7.5 PCP 496 N N N — — UnassignedDPPIII 737 N N N — — Clan SC, DPPIV 766 100 Y Y 2q24.3 7.5-8.0 FamilyS9, DPPVI 865 52 Y Mutation 7 — Subfamily B FAP 760 70 Y Y 2q23 7.5-8.0DPRP-1 882 41 N Y 15q22.1-15q22.2 7.5-8.0 DPRP-2 864 39 N Y 19p13.37.5-8.0 DPRP-3 796 54 Y Mutation 2q12.3-2q14.1 —

[0015] The greatest homology between DPRP-1, DPRP-2 and DPPIV is seen inthe C-terminal sequences. On the basis of sequence homology with DPPIV(see FIG. 1), one might predict that these DPRP proteins would havefunctions that include, but are not limited to, roles as enzymes.Cloning, expression, biochemical and molecular characterization haveconfirmed this hypothesis.

[0016] The expression pattern of DPRPs and the localization tospecialized epithelial cells and plasma cells (Leydig cells, prostateepithelial cells, lymphocytes, B cells) is consistent with a role indifferentiation, proliferation and inflammation. The localization of theDPRP-1 gene in hormone sensitive cancers (breast, prostate, testicular),tissues regulated by testosterone and the abundant expression in poorlydifferentiated cancers, demonstrate that DPRP-activating or inhibitingmolecules will have numerous therapeutic applications in the treatmentof disorders characterized by disregulated growth, differentiation andsteroid or polypeptide hormone synthesis and degradation. Data disclosedherein supports the hypothesis that DPRP-1 and DPRP-2 are involved inthe regulation of proliferation of in vitro models of prostate andtestis cancer well known to those skilled in the art.

[0017] DPRP-1 and DPRP-2 activities described herein and theirexpression patterns are compatible with their having functional roles asphysiological regulators of the immune and neuroendocrine systemsthrough the enzymatic modification of biochemical mediators likepeptides and chemokines. The numerous functions previously described orDPPIV based upon the use of inhibitors may be due in part to its actionand that of similar proteins, like the DPRPs. Therefore, the discoveryof selective and potent inhibitors of DPPIV, of the DPRPs and of otherrelated proteases like FAP is considered central to achieving effectiveand safe pharmaceutical use of these and any newly identified serineprotease inhibitors, as well as other active compounds that modify thefunction(s) of such proteins.

[0018] The invention thus provides novel proteins or polypeptides, thenucleic acids coding therefor, cells which have been modified with thenucleic acid so as to express these proteins, antibodies to theseproteins, a screening method for the discovery of new therapeutic agentswhich are inhibitors of the activity of these proteins (or which areinhibitors of DPPIV and not of the proteins), and therapeutic agentsdiscovered by such screening methods. The novel proteins and the nucleicacids coding therefor can be used to discover new therapeutic agents forthe treatment of certain diseases, such as for example, reproductive,inflammatory and metabolic disorders and also in the preparation ofantibodies with therapeutic or diagnostic value.

[0019] In accordance with one aspect of the present invention, there areprovided novel, mature, biologically active proteins, principally ofhuman origin. Such proteins may be isolated in small quantities fromsuitable animal (including human) tissue or biological fluids bystandard techniques; however, larger quantities are more convenientlyprepared in cultures of cells genetically modified so as to express theprotein.

[0020] In accordance with another aspect of the present invention, thereare provided isolated nucleic acid molecules encoding polypeptides ofthe present invention including mRNAs, DNAs, cDNAs, genomic DNAsthereof.

[0021] In accordance with a further aspect of the present invention,nucleic acid probes are also provided comprising nucleic acid moleculesof sufficient length to specifically hybridize to a nucleic acidsequence of the present invention.

[0022] In accordance with a still further aspect of the presentinvention, processes utilizing recombinant techniques are provided forproducing such polypeptides useful for in vitro scientific research, forexample, synthesis of DNA and manufacture of DNA vectors. Processes forproducing such polypeptides include culturing recombinant prokaryoticand/or eukaryotic host cells that have been transfected with DNA vectorscontaining a nucleic acid sequence encoding such a polypeptide and/orthe mature protein under conditions promoting expression of such proteinand subsequent recovery of such protein or a fragment of the expressedproduct.

[0023] In accordance with still another aspect, the invention providesmethods for using DPRP polypeptides and polynucleotides, including thetreatment of infections, such as bacterial, fungal, protozoan and viralinfections, particularly infections caused by HIV-1 or HIV-2, pain,diabetes, precocious puberty, infertility, obesity, anorexia, bulimia,Parkinson's disease, acute heart failure, hypotension, hypertension,urinary retention, osteoporosis, angina pectoris, myocardial infarction,stroke, ulcers, asthma, allergies, benign prostatic hypertrophy, cancersincluding hormone-sensitive and androgen-independent cancers, migraines,vomiting, psychotic and neurological disorders, including anxiety,schizophrenia, manic depression, depression, dementia, and severe mentalretardation, and dyskinesias, hereinafter collectively referred to as“the Diseases”.

[0024] In accordance with yet another aspect of the present invention,there is provided a process for utilizing such polypeptides, orpolynucleotides encoding such polypeptides, for the discovery ofcompounds that inhibit the biological activity of the mature proteinsthereof, e.g. by cleaving an N-terminal dipeptide, and such inhibitorsare thus also provided.

[0025] These and other aspects of the present invention should beapparent to those skilled in the art from the detailed description whichfollows.

BRIEF DESCRIPTION OF THE DRAWINGS

[0026]FIGS. 1A and 1B show the co-linear alignment of DPRP-1, DPRP-2,DPRP-3 and DPPIV, with shading being supplied to indicate the same(black) or similar (gray) amino acid residues at a particular location.

[0027]FIG. 2 is similar to FIG. 1 and shows co-linear alignment of humanand mouse DPRP-2.

[0028]FIG. 3 is a graph which shows the effects of various tetrapeptideamide inhibitors on dipeptidyl peptidase enzyme activity.

[0029] FIGS. 4A-4C show the effects of three inhibitor compounds on theproliferation of PC3 prostate cancer cell lines at various doses.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0030] In accordance with an aspect of the present invention, there areprovided isolated nucleic acid sequences (polynucleotides), which encodethe mature polypeptides having the deduced amino acid sequences of thethree DPRP's (SEQ ID NOS: 1, 3 and 5).

[0031] The polynucleotides of this invention were discovered using ahuman testis cDNA library (DPRP-1), a human colon library (DPRP-2) and ahuman hypothalamus cDNA library (DPRP-3). Isolated nucleic acid forDPRP-1 contains an open reading frame encoding a protein ofapproximately 882 amino acids in length which is structurally related tohuman DPPIV, showing 26% identity, and 41% similarity over the entirehuman DPPIV protein sequence. Isolated nucleic acid for DPRP-2 containsan open reading frame encoding for a protein of approximately 864 aminoacids, which is 39% similar to the entire DPPIV amino acid sequence.Analysis of DPRP-1 and DPRP-2 primary amino acid sequence usinghydrophobicity plots predicts that these two proteins do not have atransmembrane domain. Despite this fact, it is possible that theseintracellular serine proteases are secreted upon cellular activation.Quiescent cell proline dipeptidase (QPP) is a serine protease that istargeted to intracellular vesicles that are distinct from lysosomes(Chiravuri M, et al., J. Immunol. Nov. 15, 2000;165(10):5695-702). Thishypothesis expands the potential site(s) and scope of DPRP-1 and DPRP-2involvement in mechanisms for post-translational regulation ofchemokines, cytokines, peptides and polypeptides. The full length DPRP-3sequence contains 796 amino acids, a signal peptide from 1 to 48, and atransmembrane domain between 34 and 56. The mature protein is predictedto be a type II membrane protein and may be cleaved to produce a solubleform. The amino acid sequence is set forth in SEQ ID NO: 5, which wasdeduced from SEQ ID NO: 6 and has 54% similarity with DPPIV.

[0032] Amino acid sequence alignments of these polypeptides with membersof the prolyloligopeptidase enzyme subfamily S9B show that all threeDPRP proteins have overall sequence and structural homology to DPPIV andFAP. DPRPs are predicted to be a members of the enzyme Clan SC (Serinenucleophile) with catalytic residues in the order Ser, Asp, His and theactive site sequence (G-W-S-Y-G). TABLE 2 Homology (i.e. similarity)between DPRP-1, DPRP-2, DPRP-3 and members of the prolyl oligopeptidasefamily S9B enzymes. DPPIV 41 DPRP-1 39 74 DPRP-2 54 39 40 DPRP-3 70 4139 52 FAP 52 40 42 68 54 DPPVI

[0033] DPRP-1, DPRP-2 and DPRP-3 do not exhibit sequence similarity withany members of the classical serine protease families, chymotrypsin andsubtilisin. The order of the catalytic triad residues is different inthe three main related SC clan families: His-Asp-Ser in chymotrypsin,Asp-His-Ser in subtilisin and Ser-Asp-His in the prolyl oligopeptidases.

[0034] As shown in Table 2, DPRP-3 has the highest homology with DPPVI(68% homology and 51% identity). Wada et al isolated cDNA clones forDPPVI, a DPPIV-elated protein, from bovine, rat (Wada et al., Proc. Nat.Acad. Sci. 89: 197-201. (1992)) and human (Yokotani et al., Hum. Molec.Genet. 2:1037-1039 (1993)) brain libraries. They demonstrated that,unlike DPPIV, the catalytic triad in DPPVI does not have the firstserine residue. In DPRP-3 two of the amino acids in the catalytic triadcharacteristic of the serine protease family are conserved. However, theserine residue itself is replaced by glycine. While the absence of theserine residue is likely to prevent protease activity at this site, itis possible that multiple other functions mediated by other functionaldomains of the protein remain intact.

[0035] As briefly described above, DPPIV is a multifunctional moleculethat exerts important functions depending on the expressed cells andtissues, in addition to its catalytic activity as a peptidase. DPRP-3and DPPVI are also likely to maintain multiple functions despite theabsence of an intact catalytic triad. For example, DPPVI has beenimplicated in the regulation of neuronal plasticity. DPPVI is highlyexpressed in the hippocampus, thalamus, hypothalamus and stiatum. Inaddition, developmental arrest and embryonic lethality of rump whiteRw/Rw embryos is thought to be due to disruption of the DPPIV gene. Rwmutation is associated with a chromosomal inversion spanning 30 cM ofthe proximal portion of mouse chromosome 5. Genomic analysis of theDPPVI gene on the Rw chromosome places the inversion breakpoint in thecoding region resulting in loss of a significant fraction of theC-terminal region, Hough R. B. et al., Proc. Nat. Acad. Sci., 95,13800-13805 (1998).

[0036] The human DPRP-1 gene, predicted to be 32668 bp in length, has atleast 22 exons and eight transcripts. It maps to chromosome 15(NT_(—)010265) at position 15q21.1-15q22.1. The lengths of predictedalternative splice variant transcripts vary between 602 bp and 4523 bp(see SEQ ID NOS: 7-22). This is in agreement with the multipletranscripts observed by Northern blot analysis (See Example 2). ESTsrepresenting the transcripts were found in numerous tissues includingsenescent fibroblasts, T-lymphocytes, germinal center B-cells, germ cellseminoma, testis, melanocytes, uterus, ovary breast, multiple sclerosislesions, pancreas and placenta.

[0037] Human DPRP-2 belongs to a gene with at least 27 exons and ninesplice variants (see SEQ ID NOS: 23-40). One SNP was observed in the 3′UTR. (88% (37) C vs. 12% (5) T). The DPRP-2 gene maps to region 19p13.3of chromosome 19. This location is host to a number of disease markersand is associated with various disorders including hypocalciurichypercalcemia, type II cerebellar ataxia, muscular dystrophy,convulsions, susceptibility to atherosclerosis, psoriasis, ectodermaldysplasia, and acute myeloid leukemia. In agreement with the ubiquitousdistribution of the mRNA observed by Northern blot analysis (see Example2), DPRP-2 was expressed in a wide variety of tissues upon examinationof EST's coverage (e.g. over 64 EST's expressed in liver, spleen,muscle, melanocytes, heart, lung, placenta, skin, pancreas, stomach,brain parathyroid gland).

[0038] Human DPRP-3 belongs to a gene with at least 23 exons and twosplice variants (see SEQ ID NOS: 41-44). The gene maps to chromosome 2(NT_(—)005445) at position 2q12.3-2q14.1. Transcripts for DPRP-3 did notshow as wide a distribution as DPRP-1 and DPRP-2. As shown by Northernblot in Example 2, DPRP-3 expression is restricted to brain andpancreas. ESTs representing the DPRP-3 mRNA were abundant in tissuederived from multiple sclerosis lesions, hypothalamus, whole brain andnerves, with a few transcripts being found in uterus and colon.

[0039] The relationships among human and rodent proteases in clan SC,including DPRP-1 DPRP-2 and DPRP-3, were analyzed using Neighbor Joiningmethod (NJ), see Saitou and Nei, Mol. Biol. Evol., 4, 406-525 (1987).Phylogenetic analysis shows that among the S9 proteases, DPRP-1 andDPRP-2, both lacking a transmembrane domain, are distinguished fromDPPIV and its closely related proteins like FAP. Similarity is shownhowever between DPPIV and FAP and between DPRP-3 and DPPVI, which areall type II membrane proteins.

[0040] A database search for additional DPRP-related genes revealed thepresence of a murine sequence related to DPRP-1. Alignment of this mousesequence with the novel human proteases shows that the mDPRP-1 displaysconsiderable homology with its human counterpart (FIG. 2). One skilledin the art will readily recognize that the novel mouse protease gene canbe isolated using the sequence information disclosed herein and can bereadily incorporated into one of the routinely used expressionconstructs which are well known in the art. Use of this disclosedsequence by those skilled in the art to generate a transgenic mousemodel will employ development of gene-targeting vectors, for example,that result in homologous recombination in mouse embryonic stem cells.The use of knockout mice in further analysis of the function of DPRPgenes is a valuable tool.

[0041] The polynucleotides of the present invention may be in the formof RNA or in he form of DNA; DNA should be understood to include cDNA,genomic DNA, and synthetic DNA. The DNA may be double-stranded orsingle-stranded and, if single-stranded, may be the coding strand ornon-coding (antisense) strand. The coding sequence which encodes themature polypeptide may be identical to the coding sequence shown in SEQID NOS: 2, 4 and 6 respectively, or it may be a different codingsequence encoding the same mature polypeptide, as a result of theredundancy or degeneracy of the genetic code or a single nucleotidepolymorphism. For example, it may also be an RNA transcript whichincludes the entire length of any one of SEQ ID NOS: 2, 4 and 6.

[0042] The polynucleotides which encode the mature proteins of SEQ IDNOS: 1, 3, 5, respectively, may include but are not limited to thecoding sequence for the mature protein alone; the coding sequence forthe mature polypeptide plus additional coding sequence, such as a leaderor secretory sequence or a proprotein sequence; and the coding sequencefor the mature protein (and optionally additional coding sequence) plusnon-coding sequence, such as introns or a non-coding sequence 5′ and/or3′ of the coding sequence for the mature protein.

[0043] Thus, the term “polynucleotide encoding a polypeptide” or theterm “nucleic acid encoding a polypeptide” should be understood toencompass a polynucleotide or nucleic acid which includes only codingsequence for the mature protein as well as one which includes additionalcoding and/or non-coding sequence. The terms polynucleotides and nucleicacid are used interchangeably.

[0044] The present invention also includes polynucleotides where thecoding sequence for the mature protein may be fused in the same readingframe to a polynucleotide sequence which aids in expression andsecretion of a polypeptide from a host cell; for example, a leadersequence which functions as a secretory sequence for controllingtransport of a polypeptide from the cell may be so fused. Thepolypeptide having such a leader sequence is termed a preprotein or apreproprotein and may have the leader sequence cleaved, by the host cellto form the mature form of the protein. These polynucleotides may have a5′ extended region so that it encodes a proprotein, which is the matureprotein plus additional amino acid residues at the N-terminus. Theexpression product having such a prosequence is termed a proprotein,which is an inactive form of the mature protein; however, once theprosequence is cleaved an active mature protein remains. Thus, forexample, the polynucleotides of the present invention may encode matureproteins, or proteins having a prosequence, or proteins having both aprosequence and a presequence (leader sequence).

[0045] The polynucleotides of the present invention may also have thecoding sequence used in frame to a marker sequence which allows forpurification of the polypeptides of he present invention. The markersequence may be a polyhistidine tag, a hemagglutinin (HA) tag, a c-myctag or a V5 tag when a mammalian host, e.g. COS-1 cells, is used. The HAtag would correspond to an epitope derived from the influenzahemagglutinin protein (Wilson, I., et al., Cell, 37:767 (1984)), and thec-myc tag may be an eptitope from human Myc protein (Evans, G. I. etal., Mol. Cell. Biol. 5: 3610-3616 (1985)).

[0046] The term “gene” means the segment of DNA involved in producing apolypeptide chain; it includes regions preceding and following thecoding region (leader and trailer) as well as intervening sequences(introns) between individual coding segments (exons). The term“significant sequence homology” is intended to denote that at least 25%,preferably at least 40%, of the amino acid residues are conserved, andthat, of the non-conserved residues, at least 40% are conservativesubstitutions.

[0047] Fragments of the full-length genes of the present invention maybe used as a hybridization probe for a cDNA library to isolatefull-length cDNA as well as to isolate other cDNAs which havesignificant sequence homology to the gene and will encode proteins orpolypeptides having similar biological activity or function. By similarbiological activity or function, for purposes of this application, ismeant the ability to cleave an N-terminal dipeptide having Ala or Pro asthe penultimate residue or other amino acids. Such a probe of this typehas at least 14 bases (at least 14 contiguous nucleotides from one ofSEQ ID NOS: 2, 4 or 6), preferably at least 30 bases, and such maycontain, for example, 50 or more bases. Such probe may also be used toidentify a cDNA clone corresponding to a full-length transcript and/or agenomic clone or clones that contains the complete gene, includingregulatory and promoter regions, exons, and introns. Labelledoligonucleotides having a sequence complementary to that of the gene ofthe present invention are useful to screen a library of human cDNA,genomic DNA or mRNA to locate members of the library to which the probehybridizes. As an example, a known DNA sequence may be used tosynthesize an oligonucleotide probe which is then used in screening alibrary to isolate the coding region of a gene of interest.

[0048] The present invention is considered to further providepolynucleotides which hybridize to the hereinabove-described sequenceswherein there is at least 70%, preferably at least 90%, and morepreferably at least 95% identity or similarity between the sequences,and thus encode proteins having similar biological activity. Moreover,as known in the art, there is “similarity” between two polypeptides whenthe amino acid sequences contain the same or conserved amino acidsubstitutes for each individual residue in the sequence. Identity andsimilarity may be measured using sequence analysis software (e.g.,Sequence Analysis Software Package of the Genetics Computer Group,University of Wisconsin Biotechnology Center, 1710 University Avenue,Madison, Wis. 53705). The present invention particularly provides suchpolynucleotides which hybridize under stringent conditions to thehereinabove-described polynucleotides. As herein used, the term“stringent conditions” means conditions which permit hybridizationbetween polynucleotides sequences and the polynucleotide sequences ofSEQ ID NOS: 2, 4 and 6 where there is at least about 70% identity.Suitably stringent conditions can be defined by, e.g., theconcentrations of salt or formamide in the prehybridization andhybridization solutions, or by the hybridization temperature, and arewell known in the art. In particular, stringency can be increased byreducing the concentration of salt, by increasing the concentration offormamide, and/or by raising the hybridization temperature.

[0049] For example, hybridization under high stringency conditions mayemploy about 50% formamide at about 37° C. to 42° C., whereashybridization under reduced stringency conditions might employ about 35%to 25% formamide at about 30° C. to 35° C. One particular set ofconditions for hybridization under high stringency conditions employs42° C., 50% formamide, 5×. SSPE, 0.3% SDS, and 200 μg/ml sheared anddenatured salmon sperm DNA. For hybridization under reduced stringency,similar conditions as described above may be used in 35% formamide at areduced temperature of 35° C. The temperature range corresponding to aparticular level of stringency can be further narrowed by calculatingthe purine to pyrimidine ratio of the nucleic acid of interest andadjusting the temperature accordingly. Variations on the above rangesand conditions are well known in the art. Preferably, hybridizationshould occur only if there is at least 95%, and more preferably at least97%, identity between the sequences. The polynucleotides which hybridizeto the hereinabove described polynucleotides in a preferred embodimentencode polypeptides which exhibit substantially the same biologicalfunction or activity as the mature protein encoded by one of the cDNAsof SEQ ID NOS: 2, 4 and 6.

[0050] As mentioned, a suitable polynucleotide probe may have at least14 bases, preferably 30 bases, and more preferably at least 50 bases,and will hybridize to a polynucleotide of the present invention whichhas an identity thereto, as hereinabove described, and which may or maynot retain activity. For example, such polynucleotides may be employedas a probe for hybridizing to the polynucleotides of SEQ ID NOS: 2, 4and 6 respectively, for example, for recovery of such a polynucleotide,or as a diagnostic probe, or as a PCR primer. Thus, the presentinvention includes polynucleotides having at least a 70% identity,preferably at least a 90% identity, and more preferably at least a 95%identity to a polynucleotide which encodes the polypeptides of SEQ IDNOS: 1, 3 and 5 respectively, as well as fragments thereof, whichfragments preferably have at least 30 bases and more preferably at least50 bases, and to polypeptides encoded by such polynucleotides.

[0051] As is well known in the art, the genetic code is redundant inthat certain amino acids are coded for by more than one nucleotidetriplet (codon), and the invention includes those polynucleotidesequences which encode the same amino acids using a different codon fromthat specifically exemplified in the sequences herein. Such apolynucleotide sequence is referred to herein as an “equivalent”polynucleotide sequence. The present invention further includes variantsof the hereinabove described polynucleotides which encode for fragments,such as part or all of the mature protein, analogs and derivatives ofone of the polypeptides having the deduced amino acid sequence of SEQ IDNOS: 1, 3 and 5 respectively. The variant forms of the polynucleotidesmay be a naturally occurring allelic variant of the polynucleotides or anon-naturally occurring variant of the polynucleotides. For example, thevariant in the nucleic acid may simply be a difference in codon sequencefor the amino acid resulting from the degeneracy of the genetic code, orthere may be deletion variants, substitution variants and addition orinsertion variants. As known in the art, an allelic variant is analternative form of a polynucleotide sequence which may have asubstitution, deletion or addition of one or more nucleotides that doesnot substantially alter the biological function of the encodedpolypeptide.

[0052] The present invention further includes polypeptides which havethe deduced amino acid sequence of SEQ ID NOS: 1, 3 and 5, as well asfragments, analogs and derivatives of such polypeptides. The terms“fragment,” “derivative” and “analog”, when referring to thepolypeptides of SEQ ID NOS: 1, 3 and 5, means polypeptides that retainessentially the same biological function or activity as suchpolypeptides. An analog might, for example, include a proprotein whichcan be activated by cleavage of the proprotein portion to produce anactive mature protein. The polypeptides of the present invention may berecombinant polypeptides, natural polypeptides or synthetic polypeptide;however, they are preferably recombinant polypeptides, glycosylated orunglycosylated.

[0053] The fragment, derivative or analog of a polypeptide of SEQ IDNOS: 1, 3 and 5 respectively, may be (i) one in which one or more of theamino acid residues is substituted with a conserved or non-conservedamino acid residue (preferably a conserved amino acid residue) and suchsubstituted amino acid residue may or may not be one encoded by thegenetic code, or (ii) one in which one or more of the amino acidresidues includes a substituent group, or (iii) one in which additionalamino acids are fused to the mature protein, such as a leader orsecretory sequence or a sequence which is employed for purification ofthe mature polypeptide or a proprotein sequence. Such fragments,derivatives and analogs are deemed to be within the scope of thoseskilled in the art to provide upon the basis of the teachings herein.

[0054] The polypeptides and polynucleotides of the present inventionshould be in an isolated form, and preferably they are purified tosubstantial homogeneity or purity. By substantial homogeneity is meant apurity of at least about 85%.

[0055] The term “isolated” is used to mean that the material has beenremoved from its original environment (e.g., the natural environment ifit is naturally occurring). For example, a naturally occurringpolynucleotide or polypeptide present in a living animal is notconsidered to be isolated, but the same polynucleotide or polypeptide,when separated from substantially all of the coexisting materials in thenatural system, is considered isolated. For DNA, the term includes, forexample, a recombinant DNA which is incorporated into a vector, into anautonomously replicating plasmid or virus, or into the genomic DNA of aprokaryote or eukaryote; or which exists as a separate molecule (e.g., acDNA or a genomic or cDNA fragment produced by polymerase chain reaction(PCR) or restriction endonuclease digestion) independent of othersequences. It also includes a recombinant DNA which is part of a hybridgene encoding additional polypeptide sequence, e.g., a fusion protein.Further included is recombinant DNA which includes a portion of thenucleotides shown in one of SEQ ID NO: 2, 4 or 6 which encodes analternative splice variant of the DPRP. Various alternative splicevariants are exemplified in SEQ ID NOS: 8, 10, 12, 14, 16, 18, 20, 22,24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44 and 46.

[0056] The polypeptides of the present invention include any one of thepolypeptide of SEQ ID NOS: 1, 3 and 5 (in particular the matureprotein), as well as polypeptides which have at least 70% similarity(e.g. preferably at least 60% and more preferably at least 70% identity)to one of the polypeptides of SEQ ID NOS: 1, 3 and 5, more preferably atleast 90% similarity (e.g. preferably at least 90% identity) to one ofthe polypeptides of SEQ ID NOS: 1, 3 and 5, and most preferably at least95% similarity (e.g. preferably at least 95% identity) to one of thepolypeptides of SEQ ID NOS: 1, 3 and 5. Moreover, they should preferablyinclude exact portions of such polypeptides containing a sequence of atleast 30 amino acids, and more preferably at least 50 amino acids.

[0057] Fragments or portions of the polypeptides of the presentinvention may be employed as intermediates for producing thecorresponding full-length polypeptides by peptide synthesis. Fragmentsor portions of the polynucleotides of the present invention may also beused to synthesize full-length polynucleotides of the present invention.

[0058] The present invention also includes vectors which include suchpolynucleotides, host cells which are genetically engineered with suchvectors and the production of polypeptides by recombinant techniquesusing the foregoing. Host cells are genetically engineered (transducedor transformed or transfected) with such vectors which may be, forexample, a cloning vector or an expression vector. The vector may be,for example, in the form of a plasmid, a viral particle, a phage, etc.The engineered host cells can be cultured in conventional nutrient mediamodified as appropriate for activating promoters, selectingtransformants or amplifying the genes of the present invention. Theculture conditions, such as temperature, pH and the like, are thosecommonly used with the host cell selected for expression, as well knownto the ordinarily skilled artisan.

[0059] The polynucleotides of the present invention may be employed forproducing polypeptides by recombinant techniques. Thus, for example, thepolynucleotides may be included in any one of a variety of expressionvectors for expressing polypeptides. Such vectors include chromosomal,nonchromosomal and synthetic DNA sequences, e.g., derivatives of SV40;bacterial plasmids; phage DNA; baculovirus; yeast plasmids; vectorsderived from combinations of plasmids and phage DNA, viral DNA such asvaccinia, adenovirus, fowl pox virus, and pseudorabies. However, anyother vector may be used as long as it is replicable and viable in thehost.

[0060] The appropriate DNA sequence may be inserted into the vector byany of a variety of procedures. In general, the DNA sequence is insertedinto an appropriate restriction endonuclease site(s) by procedures wellknown in the art, which procedures are deemed to be within the scope ofthose skilled in this art.

[0061] The DNA sequence in the expression vector is operatively linkedto an appropriate expression control sequence(s) (promoter) to directmRNA synthesis. As representative examples of such promoters, there maybe mentioned: LTR or SV40 promoter, the E. coli. lac or trp, the phagelambda P.sub.L promoter and other promoters known to control expressionof genes in prokaryotic or eukaryotic cells or their viruses. Theexpression vector should also contain a ribosome binding site fortranslation initiation and a transcription terminator. The vector mayalso include appropriate sequences for amplifying expression. Inaddition, the expression vectors preferably contain one or moreselectable marker genes to provide a phenotypic trait for selection oftransformed host cells, such as dihydrofolate reductase orneomycin-resistance for eukaryotic cell culture, or such astetracycline- or ampicillin-resistance in E. coli.

[0062] The vector containing the appropriate DNA sequence as hereinabovedescribed, as well as an appropriate promoter or control sequence, maybe employed to transform an appropriate host to permit the host toexpress the protein. As representative examples of appropriate hosts,there may be mentioned: bacterial cells, such as E. coli, Streptomyces,Salmonella typhimurium; fungal cells, such as yeast; insect cells, suchas Drosophila S2 and Spodoptera Sf9; animal cells, such as CHO, COS orBowes melanoma; adenoviruses; plant cells, etc. The selection of anappropriate host is deemed to be within the scope of those skilled inthe art from the teachings herein.

[0063] Synthetic production of nucleic acid sequences is well known inthe art as is apparent from CLONTECH 95/96 Catalogue, pages 215-216,CLONTECH, 1020 East Meadow Circle, Palo Alto, Calif. 94303. Thus, thepresent invention also includes expression vectors useful for theproduction of the proteins of the present invention

[0064] The present invention further includes recombinant constructscomprising one or more of the sequences as broadly described above. Theconstructs may comprise a vector, such as a plasmid or viral vector,into which a sequence of the invention has been inserted, in a forwardor reverse orientation. In a preferred aspect of this embodiment, theconstruct further comprises regulatory sequences, including, forexample, a promoter, operably linked to the sequence. Large numbers ofsuitable vectors and promoters are known to those of skill in the art,and are commercially available. The following vectors are provided byway of example: Bacterial: pQE70, pQE60, pQE-9 (Qiagen), pBS, pD10,phagescript, psiX174, pbluescript SK, pbsks, pNH8A, pNH16a, pNH18A,pNH46A (Stratagene), ptrc99a, pKK223-3, pKK233-3, pDR540 and pRIT5(Pharmacia); and Eukaryotic: pWLNEO, pSV2CAT, pOG44, pXT1, pSG(Stratagene) pSVK3, pBPV, pMSG, and pSVL (Pharmacia). However, any othersuitable plasmid or vector may be used as long as it is replicable andviable in the host.

[0065] Promoter regions can be selected from any desired gene using CAT(chloramphenicol acetyl transferase) vectors or other vectors withselectable markers. Two appropriate vectors are pKK232-8 and pCM7.Particular named bacterial promoters include lacI, lacZ, T3, T7, gpt,lambda P.sub.R, P.sub.L and trp. Eukaryotic promoters include CMVimmediate early, HSV thymidine kinase, early and late SV40, LTRs fromretrovirus, and mouse metallothionein-I. Selection of the appropriatevector and promoter is well within the level of ordinary skill in theart.

[0066] Components of the expression vector may generally include: 1) aneomycin phosphotransferase (G418), or hygromycin B phosphotransferase(hyg) gene as a selection marker, 2) an E. coli origin of replication,3) a T7 and SP6 phage promoter sequence, 4) lac operator sequences, 5)the lactose operon repressor gene (lacIq) and 6) a multiple cloning sitelinker region. Such an origin of replication (oriC) may be derived frompUC19 (LTI, Gaithersburg, Md.).

[0067] A nucleotide sequence encoding one of the polypeptides SEQ IDNOS: 2, 4 and 6 having the appropriate restriction sites is generated,for example, according to the PCR protocol described in Example 1hereinafter, using PCR primers having restriction sites for KpnI (as the5′ primer) and NotI or SacI (as the 3′ primer) for DPRP-1, or sites forHindIII (as the 5′ primer) and NotI or BamHI (as the 3′ primer) forDPRP-2. The PCR inserts are gel-purified and digested with compatiblerestriction enzymes. The insert and vector are ligated according tostandard protocols.

[0068] In a further embodiment, the present invention provides hostcells containing the above-described constructs. The host cell can be ahigher eukaryotic cell, such as a mammalian cell, or a lower eukaryoticcell, such as a yeast cell, or the host cell can be a prokaryotic cell,such as a bacterial cell. Introduction of the construct into the hostcell can be effected by calcium phosphate transfection, DEAE-Dextranmediated transfection, lipofection or electroporation (Davis, L.,Dibner, M., Battey, I., Basic Methods in Molecular Biology, (1986)).

[0069] Such constructs in host cells are preferably used in aconventional manner to produce the gene product encoded by therecombinant sequence. Alternatively, the polypeptides of the inventioncan be synthetically produced by conventional peptide synthesizers or bychemical ligation of suitable fragments thus prepared.

[0070] Mature proteins can be expressed in mammalian cells, yeast,bacteria, or other cells under the control of appropriate promoters.Cell-free translation systems can also be employed to produce suchproteins using RNAs derived from the DNA constructs of the presentinvention. Appropriate cloning and expression vectors for use withprokaryotic and eukaryotic hosts are described by Sambrook, et al.,Molecular Cloning: A Laboratory Manual, Second Edition, Cold SpringHarbor, N.Y., (1989), the disclosure of which is hereby incorporated byreference.

[0071] Transcription of the DNA encoding the polypeptides of the presentinvention by higher eukaryotes is increased by inserting an enhancersequence into the vector. Enhancers include cis-acting elements of DNA,usually about from 10 to 300 bp, that act on a promoter to increase itstranscription. Examples include the SV40 enhancer on the late side ofthe replication origin bp 100 to 270, a cytomegalovirus early promoterenhancer, the polyoma enhancer on the late side of the replicationorigin, and adenovirus enhancers.

[0072] Generally, recombinant expression vectors will include origins ofreplication and selectable markers permitting transformation of the hostcell, e.g., the ampicillin-resistance gene of E. coli and S. cerevisiaeTRP1 gene, and a promoter derived from a highly expressed gene to directtranscription of a downstream structural sequence. Such promoters can bederived from operons encoding glycolytic enzymes, such as3-phosphoglycerate kinase (PGK), alpha-factor, acid phosphatase, or heatshock proteins, among others. The heterologous structural sequence isassembled in appropriate phase with translation initiation andtermination sequences, and preferably, a leader sequence capable ofdirecting secretion of translated protein into the periplasmic space orextracellular medium. Optionally, the heterologous sequence can encode afusion protein including an N-terminal identification peptide impartingdesired characteristics, e.g., stabilization or simplified purificationof expressed recombinant product.

[0073] Useful expression vectors for bacterial use are constructed byinserting a structural DNA sequence encoding a desired protein togetherwith suitable translation initiation and termination signals in operablereading phase with a functional promoter. The vector will comprise oneor more phenotypic selectable markers and an origin of replication toensure maintenance of the vector and to, if desired, provideamplification within the host. Suitable prokaryotic hosts fortransformation include E. coli, Bacillus subtilis, Salmonellatyphimurium and various species within the genera Pseudomonas,Streptomyces, and Staphylococcus, although others may also be employedas a matter of choice.

[0074] As a representative but non-limiting example, useful expressionvectors for bacterial use can comprise a selectable marker and bacterialorigin of replication derived from commercially available plasmidscomprising genetic elements of the well known cloning vector pBR322(ATCC 37017). Such commercial vectors include, for example, pKK223-3(Pharmacia Fine Chemicals, Uppsala, Sweden) and GEM1 (Promega Biotec,Madison, Wis., U.S.A.). These pBR322 “backbone” sections are combinedwith an appropriate promoter and the structural sequence to beexpressed.

[0075] Following transformation of a suitable host strain and growth ofthe host strain to an appropriate cell density, the selected promoter isinduced by appropriate means (e.g., temperature shift or chemicalinduction), and cells are cultured for an additional period. Cells aretypically harvested by centrifugation and then disrupted by physical orchemical means, with the resulting crude extract being retained forfurther purification. Microbial cells employed in expression of proteinscan be disrupted by any convenient method, including freeze-thawcycling, sonication, mechanical disruption and use of cell-lysingagents; such methods are well known to those skilled in the art.

[0076] Various mammalian cell culture systems can also be employed toexpress a recombinant protein. Examples of mammalian expression systemsinclude the COS-7 lines of monkey kidney fibroblasts, described byGluzman, Cell 23:175 (1981). Other cell lines capable of expressing acompatible vector include, for example, the C127, 3T3, CHO, HeLa and BHKcell lines. Mammalian expression vectors will generally comprise anorigin of replication, a suitable promoter and enhancer, and also anynecessary ribosome binding sites, polyadenylation site, splice donor andacceptor sites, transcriptional termination sequences, and 5′ flankingnontranscribed sequences. DNA sequences derived from the SV40 splice,and polyadenylation sites may be used to provide required nontranscribedgenetic elements.

[0077] The polypeptides can be recovered and purified from recombinantcell cultures by methods including ammonium sulfate or ethanolprecipitation, acid extraction, anion or cation exchange chromatography,phosphocellulose chromatography, hydrophobic interaction chromatography,affinity chromatography, hydroxylapatite chromatography and lectinchromatography. Recovery can be facilitated if the polypeptide isexpressed at the surface of the cells, but such is not a prerequisite.Recovery may also be desirable of cleavage products that are cleavedfollowing expression of a longer form of the polypeptide. Proteinrefolding steps as known in this art can be used, as necessary, tocomplete configuration of the mature protein. High performance liquidchromatography (HPLC) can be employed for final purification steps.

[0078] The polypeptides of the present invention may be purified naturalproducts, or produced by recombinant techniques from a prokaryotic oreukaryotic host (for example, by bacterial, yeast, higher plant, insector mammalian cells in culture). Depending upon the host employed in arecombinant production procedure, the polypeptides of the presentinvention may be glycosylated or may be non-glycosylated. Polypeptidesof the invention may also include an initial methionine amino acidresidue.

[0079] In a preferred embodiment, the proteins of the invention areisolated and purified so as to be substantially free of contaminationfrom other proteins. For example, the proteins of the invention shouldconstitute at least 80% by weight of the total protein present in asample, more preferably at least 90%, even more preferably at least 95%,and most preferably at least 98% by weight of the total protein.

[0080] These proteins may be in the form of a solution in water, anothersuitable solvent, such as dimethyl sulphoxide (DMSO) or ethanol, or amixture of suitable solvents. Examples of mixtures of solvents include10% (by weight) ethanol in water and 2% (by weight) DMSO in water. Asolution may further comprise salts, buffering agents, chaotropicagents, detergents, preservatives and the like. Alternatively, theproteins may be in the form of a solid, such as a lyophilised powder ora crystalline solid, which may also comprise a residual solvent, a saltor the like.

[0081] As used herein, the term “antibodies” includes polyclonalantibodies, affinity-purified polyclonal antibodies, monoclonalantibodies, and antigen-binding fragments, such as F(ab′)₂ and Fab′proteolytic fragments. Genetically engineered intact antibodies orfragments, such as chimeric antibodies, Fv fragments, single chainantibodies and the like, as well as synthetic antigen-binding peptidesand polypeptides, are also included. Non-human antibodies may behumanized by grafting non-human CDRs onto human framework and constantregions, or by incorporating the entire non-human variable domains(optionally “cloaking” them with a human-like surface by replacement ofexposed residues, wherein the result is a “veneered” antibody). In someinstances, humanized antibodies may retain non-human residues within thehuman variable region framework domains to enhance proper bindingcharacteristics. Through humanizing antibodies, biological half-life maybe increased, and the potential for adverse immune reactions uponadministration to humans should be reduced.

[0082] Alternative techniques for generating or selecting antibodiesuseful herein include in vitro exposure of lymphocytes to humanprohormone DPRP protein or a peptide therefrom, and selection ofantibody display libraries in phage or similar vectors (for instance,through use of immobilized or labeled human DPRP protein or peptide).Genes encoding polypeptides having potential human DPRP polypeptidebinding domains can be obtained by screening random peptide librariesdisplayed on phage (phage display) or on bacteria, such as E. coli.Nucleotide sequences encoding such polypeptides can be obtained in anumber of ways well known in this art.

[0083] As would be evident to one of ordinary skill in the art,polyclonal antibodies can be generated from inoculating a variety ofwarm-blooded animals, such as horses, cows, goats, sheep, dogs,chickens, rabbits, mice and rats, with a human DPRP polypeptide or afragment thereof. The immunogenicity of a human prohormone DPRPpolypeptide may be increased through the use of an adjuvant, such asalum (aluminum hydroxide) or Freund's complete or incomplete adjuvant,or surface active substances, such as lysolecithin, pluronic polyols,polyanions, peptides, oil emulsions, KLH or dinitrophenol. Amongadjuvants used in humans, BCG (bacilli Calmette-Guerin) andCorynebacterium parvum are especially preferable. Polypeptides usefulfor immunization also include fusion polypeptides, such as fusions ofDPRP or a portion thereof with an immunoglobulin polypeptide or withmaltose binding protein. The polypeptide immunogen may be a full-lengthmolecule or a portion thereof. If the polypeptide portion is“hapten-like”, such portion may be advantageously joined or linked to amacromolecular carrier, such as keyhole limpet hemocyanin (KLH), bovineserum albumin (BSA) or tetanus toxoid, for immunization. Antibodies toDPRP may also be generated using methods that are well known in the art.Such antibodies may include, but are not limited to, polyclonal,monoclonal, chimeric, and single chain antibodies, Fab fragments, andfragments produced by a Fab expression library. Neutralizing antibodies(i.e., those which block or modify interactions at the active sites) areespecially preferred for therapeutic use.

[0084] For the production of antibodies, binding proteins, or peptideswhich bind specifically to DPRP, libraries of single chain antibodies,Fab fragments, other antibody fragments, non-antibody protein domains,or peptides may be screened. The libraries could be generated usingphage display, other recombinant DNA methods, or peptide synthesis(Vaughan, T. J. et al. Nature Biotechnology 14: 309-314 (1966)). Suchlibraries would commonly be screened using methods which are well knownin the art to identify sequences which demonstrate specific binding toDPRP.

[0085] It is preferred that the oligopeptides, peptides, or fragmentsused to induce antibodies to DPRP have an amino acid sequence consistingof at least about 5 amino acids and, more preferably, of at least about10 amino acids. It is also preferable that these oligopeptides,peptides, or fragments are identical to a portion of the amino acidsequence of the natural protein. Short stretches of DPRP amino acids mayalso be fused with those of another protein, such as KLH, and antibodiesto the chimeric molecule may be produced.

[0086] Monoclonal antibodies to DPRP may be prepared using any wellknown technique which provides for the production of antibody moleculesby continuous cell lines in culture. These include, but are not limitedto, the hybridoma technique, the human B-cell hybridoma technique, andthe EBV-hybridoma technique, although monoclonal antibodies produced byhybridoma cells may be preferred.

[0087] In addition, techniques developed for the production of “chimericantibodies”, such as the splicing of mouse antibody genes to humanantibody genes to obtain a molecule with appropriate antigen specificityand biological activity, can be used, see Neuberger, M. S. et al. Nature312: 604-608 (1984). Alternatively, techniques described for theproduction of single chain antibodies may be adapted, using methodsknown in the art, to produce DPRP-specific single chain antibodies.Antibodies with related specificity, but of distinct idiotypiccomposition, may be generated by chain shuffling from randomcombinatorial immunoglobulin libraries. (Burton D. R. Proc. Natl. Acad.Sci. 88: 11120-11123 (1991)).

[0088] Antibodies may also be produced by inducing in vivo production inthe lymphocyte population or by screening immunoglobulin libraries orpanels of highly specific binding reagents as disclosed in theliterature. (Orlandi, R. et al. Proc. Natl. Acad. Sci. 86: 3833-3837(1989)).

[0089] Antibody fragments which contain specific binding sites for DPRPmay also be generated. For example, such fragments include, but are notlimited to, F(ab′)₂ fragments produced by pepsin digestion of theantibody molecule and Fab fragments generated by reducing the disulfidebridges of the F(ab′)₂ fragments. Alternatively, Fab expressionlibraries may be constructed to allow rapid and easy identification ofmonoclonal Fab fragments with the desired specificity. (Huse, W. D. etal. Science 254: 1275-1281 (1989)).

[0090] Various immunoassays may be used to identify antibodies havingthe desired specificity. Numerous protocols for competitive binding orimmunoradiometric assays using either polyclonal or monoclonalantibodies with established specificities are well known in the art.Such immunoassays typically involve the measurement of complex formationbetween DPRP and its specific antibody. A two-site, monoclonal-basedimmunoassay utilizing monoclonal antibodies reactive to twonon-interfering DPRP epitopes is preferred, but a competitive bindingassay may also be employed.

[0091] As earlier mentioned, the DPRPs can be used in treatment of theDiseases. Pharmaceutical compositions suitable for use in this aspect ofthe invention include compositions wherein the active ingredients arecontained in an effective amount to achieve the intended purposerelating to one of the Diseases. The determination of a therapeuticallyeffective dose is well within the capability of those skilled in the artand can be estimated initially either in cell culture assays, e.g. ofneoplastic cells, or in animal models, usually mice, rats, rabbits,dogs, or pigs. An animal model may also be used to determine theappropriate concentration range and route of administration, whichinformation is then commonly used to determine useful doses and routesfor administration in humans.

[0092] A therapeutically effective dose refers to that amount of activeingredient, e.g. a DPRP or fragment thereof, antibodies of DPRP, or anagonist, antagonist or inhibitor of DPRP, which ameliorates particularsymptoms or conditions of the Disease. For example, the amount to beadministered may be effective to cleave a desired target substrate uponcontact therewith. Therapeutic efficacy and toxicity may likewise bedetermined by standard pharmaceutical procedures in cell cultures orwith experimental animals, such as by calculating the ED50 (the dosetherapeutically effective in 50% of the population) or LD50 (the doselethal to 50% of the population) statistics. The dose ratio of toxic totherapeutic effects is the therapeutic index, and it can be expressed asthe LD50/ED50 ratio. Pharmaceutical compositions which exhibit largetherapeutic indices are preferred. The data obtained from cell cultureassays and animal studies is used in formulating a range of dosage forhuman use. The dosage contained in such compositions is preferablywithin a range of circulating concentrations that include the ED50 withlittle or no toxicity. The dosage varies within this range dependingupon the dosage form employed, the sensitivity of the patient, and theroute of administration.

[0093] An exact dosage will normally be determined by the medicalpractitioner in light of factors related to the subject requiringtreatment, with dosage and administration being adjusted to provide asufficient level of the active moiety or to maintain a desired effect.Factors to be taken into account include the severity of the diseasestate, the general health of the subject, the age, weight, and gender ofthe subject, diet, time and frequency of administration, drugcombination(s), reaction sensitivities, and tolerance/response totherapy. Long-acting pharmaceutical compositions may be administeredevery 3 to 4 days, every week, or even once every two weeks, dependingon the half-life and clearance rate of the particular formulation.

[0094] Yet another aspect of the invention provides polynucleotidemolecules having sequences that are antisense to mRNA transcripts ofDPRP1, DPRP2 and DPRP-3 polynucleotides. Administration of an antisensepolynucleotide molecule can block the production of the protein encodedby DPRP-1, DPRP2 or DPRP-3. The techniques for preparing antisensepolynucleotide molecules and administering such molecules are known inthe art. For example, antisense polynucleotide molecules can beencapsulated into liposomes for fusion with cells.

[0095] In particular, the expression of DPRP-1, DPRP-2 and DPRP-3 inspecialized epithelial cells, immune cells (lymphocytes and B cells),astrocytic tumors, and in various hormone sensitive cancers providesevidence of a potential role in the pathophysiology of cancer,metaplasia and metastasis. Therefore in a further aspect, the inventionrelates to diagnostic assays for detecting diseases associated withinappropriate DPRP activity or expression levels. Antibodies thatspecifically bind DPRP may be used for the diagnosis of disorderscharacterized by expression of DPRP, or in assays to monitor patientsbeing treated with DPRP or with agonists or antagonists (inhibitors) ofDPRP. Antibodies useful for diagnostic purposes may be prepared in thesame manner as those described above for therapeutics. Diagnostic assaysfor DPRP include methods that utilize the antibody and a label to detectDPRP in human body fluids or in extracts of cells or tissues. Theantibodies may be used with or without modification, and they may belabeled by covalent or non-covalent joining with a reporter molecule. Awide variety of reporter molecules are known in the art. RecombinantDPRP proteins that have been modified so as to be catalytically inactivecan also be used as dominant negative inhibitors. Such modificationsinclude, for example, mutation of the active site.

[0096] A variety of protocols for measuring DPRP, including ELISAs, RIAsand FACS, are known in the art and provide a basis for diagnosingaltered or abnormal levels of DPRP expression. Normal or standard valuesfor DPRP expression are established by combining body fluids or cellextracts taken from normal mammalian subjects, preferably human, withantibody to DPRP under conditions suitable for complex formation. Themethod for detecting DPRP in a biological sample would comprise thesteps of: a) providing a biological sample; b) combining the biologicalsample and an anti-DPRP antibody under conditions which are suitable forcomplex formation to occur between DPRP and the antibody; and c)detecting complex formation between DPRP and the antibody, therebyestablishing the presence of DPRP in the biological sample. The amountof complex formation then may be quantified by various methods,preferably by photometric means. Quantities of DPRP expressed insubject, control, and disease samples from biopsied tissues are comparedwith the standard values. Deviation between standard and subject valuesestablishes the parameters for diagnosing disease.

[0097] In another embodiment of the invention, the polynucleotidesencoding DPRP are used for diagnostic purposes, which polynucleotidesmay include oligonucleotide sequences, complementary RNA and DNAmolecules, and PNAs. These polynucleotides may be used to detect andquantitate gene expression in biopsied tissues in which expression ofDPRP may be correlated with one of the Diseases. The diagnostic assaymay be used to distinguish between absence, presence, and excessexpression of DPRP and to monitor regulation of DPRP levels duringtherapeutic intervention. Moreover, pharmacogenomic, single nucleotidepolymorphisms (SNP) analysis of the DPRP genes can be used as a methodto screen for mutations that indicate predisposition to disease ormodified response to drugs.

[0098] DPRP polynucleotide and polypeptide sequences, fragments thereof,antibodies of DPRPs, and agonists, antagonists or inhibitors of DPRPscan be used to as discovery tools to identify molecular recognitionevents and therefore proteins, polypeptides and peptides that interactwith DPRP proteins. A specific example is phage display peptidelibraries where greater than 108 peptide sequences can be screened in asingle round of panning. Such methods as well as others are known withinthe art and can be utilized to identify compounds that inhibit orenhance DPRP-1, DPRP-2 or DPRP-3 activity. Coupled links representfunctional interactions such as complexes or pathways, and proteins thatinteract with DPRPs can be identified by a yeast two-hybrid system,proteomics (differential 2D gel analysis and mass spectrometry) andgenomics (differential gene expression by microarray or serial analysisof gene expression SAGE). Proteins identified as functionally linked toDPRPs and the process of interaction form the basis of methods ofscreening for inhibitors, agonists and antagonists and modulators ofthese DPRP-protein interactions.

[0099] The term “antagonist,” as it is used herein, refers to aninhibitor molecule which, when bound to DPRP, decreases the amount orthe duration of the effect of the biological or immunological activityof DPRP, e.g. decreasing the enzymatic activity of the peptidase tocleave the N-terminal dipeptide. Antagonists may include proteins,nucleic acids, carbohydrates, antibodies, or any other molecules whichdecrease the effect of DPRP; for example, they may include smallmolecules and organic compounds that bind to and inactivate DPRPs by acompetitive or non-competitive type mechanism. Specific examples of DPRPtetrapeptide peptidic enzyme activity inhibitors are described inExample 6 and 7. Inhibitors can be, for example, inhibitors of the DPRPprotease activity, or alternatively inhibitors of the binding activityof the DPRP to proteins with which they interact. Specific examples ofsuch inhibitors can include, for example, anti-DPRP antibodies,peptides, protein fragments, or small peptidyl protease inhibitors, orsmall non-peptide, organic molecule inhibitors which are formulated in amedium that allows introduction into the desired cell type.Alternatively, such inhibitors can be attached to targeting ligands forintroduction by cell-mediated endocytosis and other receptor mediatedevents. Such methods are described further below and can be practiced bythose skilled in the art given the DPRP nucleotide and amino acidsequences described herein.

[0100] A further use for DPRPs is for the screening of potentialantagonists for use as therapeutic agents, for example, for inhibitingbinding to DPRP, as well as for screening for agonists. DPRP, itsimmunogenic fragments, or oligopeptides thereof can be used forscreening libraries of compounds which are prospective agonists orantagonists in any of a variety of drug screening techniques. Thefragment employed in such screening may be free in solution, affixed toa solid support, borne on a cell surface, or located intracellularly.The formation of binding complexes between DPRP and the agent beingtested is then measured. Other assays to discover antagonists that willinhibit DPRP are apparent from the disclosures of U.S. Pat. Nos.6,011,155, 6,107,317, 6,110,949, 6,124,305 and 6,166,063, which describeinhibitors of DPPIV. Another worthwhile use of these DPRPs is thescreening of inhibitors of DPPIV to show that they will not haveundesired side effects by also inhibiting one or more of the DPRPs.

[0101] A method provided for screening a library of small molecules toidentify a molecule which binds DPRP generally comprises: a) providing alibrary of small molecules; b) combining the library of small moleculeswith the polypeptide of either SEQ ID NOS: 1, 3 or 5, or with a fragmentthereof, under conditions which are suitable for complex formation; andc) detecting complex formation, wherein the presence of such a complexidentifies a small molecule which binds DPRP.

[0102] One method for identifying an antagonist comprises delivering asmall molecule which binds DPRP into extracts from cells transformedwith a vector expressing DPRP along with a chromogenic substrate (e.g.Ala-Pro-AFC or Ala-Pro-AMC) under conditions where cleavage wouldnormally occur, and then assaying for inhibition of cleavage by theenzyme by monitoring changes in fluorescence, or UV light absorption, byspectrophotometry to identify molecules that inhibit cleavage. A reducedrate of reaction or total amount of fluorescence or UV light absorption,in the presence of the molecule, establishes that the small molecule isan antagonist which reduces DPRP catalytic/enzymatic activity. Once suchmolecules are identified, they may be administered to reduce or inhibitcleaving by a DPRP.

[0103] The term “agonist,” as used herein, refers to a molecule which,when bound to DPRP, increases or prolongs the duration of the effect ofDPRP. Agonists may include proteins, nucleic acids, carbohydrates, orany other molecules that bind to and modulate the effect of DPRP.Although it is less likely that small molecules will prove to beeffective DPRP agonists, a method for identifying such a small molecule,which binds DPRP as an agonist, comprises delivering a chromogenic formof a small molecule that binds DPRP into cells transformed with a vectorexpressing DPRP and assaying for fluorescence or UV light absorptionchanges by spectrophotometry. An increased amount of UV absorption orfluorescence would establish that the small molecule is an agonist thatincreases DPRP activity.

[0104] Another technique for drug screening which may be used providesfor high throughput screening of compounds having suitable bindingaffinity to the protein of interest as described in published PCTapplication WO84/03564. In this method, large numbers of different smalltest compounds are synthesized on a solid substrate, such as plasticpins or some other surface. The test compounds are reacted with DPRP, orwith fragments thereof, and then washed. Bound DPRP is then detected bymethods well known in the art. Purified DPRP can also be coated directlyonto plates for use in the aforementioned drug screening techniques.Alternatively, non-neutralizing antibodies can be used to capture thepeptide and immobilize it on a solid support.

[0105] In another embodiment, one may use competitive drug screeningassays in which neutralizing antibodies capable of binding DPRPspecifically compete with a test compound for binding DPRP. In thismanner, antibodies can be used to detect the presence of any peptidethat shares one or more antigenic determinants with DPRP.

[0106] As indicated above, by investigating the binding sites, ligandsmay be designed that, for example, have more interactions with DPRP thando its natural ligands. Such antagonist ligands will bind to DPRP withhigher affinity and so function as competitive ligands. Alternatively,synthetic or recombinant proteins homologous or analogous to the ligandbinding site of native DPRP may be designed, as may other moleculeshaving high affinity for DPRP. Such molecules should also be capable ofdisplacing DPRP and provide a protective effect.

[0107] As indicated above, the knowledge of the structures of DPRPenables synthetic binding site homologues and analogues to be designed.Such molecules will facilitate greatly the use of the binding propertiesto target potential therapeutic agents, and they may also be used toscreen potential therapeutic agents. Furthermore, they may be used asimmunogens in the production of monoclonal antibodies, which antibodiesmay themselves be used in diagnosis and/or therapy as describedhereinbefore.

[0108] Given the ubiquitous expression of several members of the prolyloligopeptidase S9B family, cell lines in which targeted gene disruptionof DPPIV, DPRP-1, DPRP-2, DPRP-3, FAP and DPPVI to establish the nullphenotype will be of great value to assist screening for selective andpotent compounds. Accordingly, the invention provides such cell linesengineered with Lox-Neo IRES tk cassette and GFP-IRES-Neo Knock-in/outcassette DNA element for constructing somatic gene targeting vectors.

EXAMPLE 1 Cloning and Expression of DPRP Genes Using the MammalianExpression System

[0109] DNA fragments encoding the full-length polypeptide DPRP-1 wereamplified using PCR oligonucleotide primers corresponding to the 5′ and3′ sequences of the gene, i.e. SEQ ID NO: 45 and NO: 46. In addition,DNA fragments encoding the full length polypeptide DPRP-2 were amplifiedusing PCR oligonucleotide primers corresponding to the 5′ and 3′sequences of that gene, i.e. SEQ ID NO: 50 and NO: 51. Furthermore, DNAfragments encoding the full length polypeptide DPRP-3 were amplifiedusing PCR oligonucleotide primers corresponding to the 5′ and 3′sequences of that gene, i.e. SEQ ID NO: 55 and NO: 56.

[0110] The three amplified sequences were respectively isolated from a0.7% agarose gel using commercially available kit (GFX PCR DNA and GelBand Purification Kit, Amersham Pharmacia Biotech Inc., Piscataway N.J.,USA). The fragments were then ligated into cloning vector, pGEM-7Zf(−)(Promega Corporation, Madison Wis., USA) and sequenced. Thecorresponding cloning constructs were respectively designatedpGEM7-DPRP1, pGEM7-DPRP2 and pGEM7-DPRP3. The DNA sequences encoding thetruncated DPRP-1 or DPRP-2 or DPRP-3 were amplified using pGEM7-DPRP1 orpGEM7-DPRP2 or pGEM7-DPRP3 as a template and PCR oligonucleotideprimers. SEQ ID NO: 45 and NO: 47 were used for DPRP-1; SEQ ID NO: 50and NO: 52 were used for DPRP-2; and SEQ ID NO: 57 and NO: 58 forDPRP-3. The amplified sequences were again isolated from a 0.7% agarosegel using the same purification kits and sub-cloned into pGEM-7Zf(−).The resulting constructs were designated pGEM7-DPRP1f, pGEM7-DPRP2f andpGEM7-DPRP3f.

[0111] To make the DPRP-1 mammalian expression construct, pGEM7-DPRP1was digested with the restriction enzymes KpnI and NotI to release thefull length DPRP-1 gene. The DNA fragment carrying the DPRP-1 gene wasgel band purified using the above kit and then inserted into expressionvector pcDNA3 (Invitrogen, Carlsbad Calif., USA) to make the nativeDPRP-1 expression construct, which was designated pcDNA-DPRP1.pGEM7-DPRP If was digested with the restriction enzymes XbaI and HindIIIto release the truncated DPRP-1f gene. The DNA fragment carrying theDPRP-1f gene was gel band purified using the above kit and then insertedinto expression vector pcDNA3.1(−)/myc-His A (Invitrogen, CarlsbadCalif., USA) to make the tagged DPRP-1 expression constructpcDNA-MycHis-DPRP1.

[0112] To make the DPRP-2 mammalian expression construct, pGEM7-DPRP2was digested with the restriction enzymes HindIII and BamHI to releasethe full length DPRP-2 gene. The DNA fragment carrying the DPRP-2 genewas gel band purified using the above kit and then inserted intoexpression vector pcDNA3 (Invitrogen, Carlsbad Calif., USA) to make thenative DPRP-2 expression construct, which was designated pcDNA-DPRP2.pGEM7-DPRP2f was digested with the restriction enzymes EcoRI and BamHIto release the truncated DPRP-2f gene. The DNA fragment carrying theDPRP-2f gene was gel band purified using the above kit and then insertedinto expression vector pcDNA3.1(−)/myc-His B (Invitrogen, CarlsbadCalif., USA) to make the tagged DPRP-2 expression construct designatedpcDNA-MycHis-DPRP2.

[0113] To make the DPRP-3 mammalian expression construct, pGEM7-DPRP3was digested with the restriction enzymes EcoRI and XhoI to release thefull length DPRP-3 gene. The DNA fragment carrying the DPRP-3 gene wasgel band purified using the above kit and then inserted into expressionvector pcDNA3 (Invitrogen, Carlsbad Calif., USA) to make the nativeDPRP-3 expression construct designated pcDNA-DPRP3. pGEM7-DPRP3f wasdigested with the restriction enzymes NheI and ApaI to release thetruncated DPRP-3f gene. The DNA fragment carrying the DPRP-3f gene wasgel band purified using the above kit and then inserted into expressionvector pcDNA3.1(−)/myc-His B (Invitrogen, Carlsbad Calif., USA) to makethe tagged DPRP-3 expression construct pcDNA-MycHis-DPRP3.

EXAMPLE 2 Expression Pattern of DPRP Genes in Human Tissues

[0114] Quantitative PCR analysis was carried out to examine the levelsof expression of the mRNAs for the polypeptides of the present inventionin human tissues. RT PCR was also carried out on a number of human celllines including but not limited to prostate cancer cells (LNCaP, PC3,DU145), the MLTC-1 line (mouse testis), and MDA-MB231 cells (breastcancer). Bands of the expected sizes for DPRP-1, DPRP-2 and DPPIV wereall expressed in the various cancer cells lines, with FAP also beingexpressed at very low levels.

Northern Blot Analysis

[0115] Northern blot analysis was performed with 2 μg poly(A)⁺ RNAisolated from eight different tissues using DPRP probes. Specifically, ahuman Multiple Tissue Northern (MTN) blot (Clontech, Palo Alto, Calif.)was probed with a 1 kb N-terminal fragment that had been radioactivelylabeled by random priming in the presence of a ³²PdCTP (A. P. Feinberget al., Anal. Biochem., 132, 6 (1983)). Hybridization was performed at68° C. overnight in ExpressHyb™ hybridization solution (Clontech, PaloAlto, Calif.). The blots were first washed at room temperature in 2times SSC and 0.05% SDS, and then washed at 60° C. (DPRP-1 & DPRP-2) and50° C. (DPRP-3) in 0.1 times SSC and 0.1% SDS.

[0116] Northern analysis showed expression of DPRP-1 in several tissueswith the most abundant signal being in testis, prostate, muscle andbrain. Testis showed 3 transcripts approximately 7.5, 4.5 and 2.5 kb inlength. The shorter mRNA species was very abundant in testis butnegligible in the other tissues tested. DPRP-2 was ubiquitouslyexpressed in every tissue with highest levels in liver and muscle and apredominant transcript at Skb. DPRP-3 expression was limited to brainand pancreas. Further analysis was conducted for the three proteases inspecific brain regions (cerebellum, cortex, medulla, spinal cord,occipital lobe, frontal lobe temporal lobe and putamen). DPRP-1 wasexpressed in all regions with low levels present in the spinal cord,while DPRP-2 was expressed in all brain regions tested.

[0117] Oligonucleotide primers SEQ ID NO: 48 and NO: 49 were used forDPRP-1 quantitative PCR, whereas oligonucleotide primers SEQ ID NO: 53and NO: 54 were used for DPRP-2 quantitative PCR. Human Multiple TissuecDNA (MTC™) Panel I and Panel II (Clontech, Palo Alto Calif., USA) wereused as normalized cDNA templates. 0.5 ng of each cDNA were used in a 25μl PCR reaction, with each primer at a final concentration of 300 nM.The PCR reaction was performed using a SYBR Green PCR Core Reagents Kit(Applied Biosystems, Foster City Calif., USA) and detected with anApplied Biosystems GeneAmp 5700 sequence detection system.Manufacturer's recommended thermal cycling parameter, e.g. 50° C. for 2min, 95° C. for 10 min followed by 40 cycles of 95° C. for 15 sec and60° C. for 1 min was used. Data obtained shows relatively high rates ofexpression for both DPRP-1 and DPRP-2 in the pancreas, ovary and testis,and a particularly high rate for DPRP-2 in the liver.

EXAMPLE 3 Production of DPRP Polyclonal Antibodies and Western Blotting

[0118] The amino acid sequence deduced from the cDNA encoding DPRP-1 wasanalyzed using DNASTAR software (DNASTAR, Inc.) to determine regions ofhigh immunogenicity, and a corresponding oligopeptide was synthesizedand used to raise anti-DPRP-1 antibodies. The procedure was repeated forDPRP-2 and DPRP-3. The selection of appropriate peptide sequences andthe techniques for antibody production are methods well known to thoseof skill in the art. Selection of appropriate epitopes, such as thosenear the C-terminus or in hydrophilic regions, is well known in thisart.

[0119] Typically, oligopeptides that are about 15 to 20 residues inlength, e.g. SEQ ID NO: 59 for DPRP-1, SEQ ID NO: 60 for DPRP-2 and SEQID NO: 61 for DPRP-3, were synthesized using an Applied BiosystemsPeptide Synthesizer Model 431 A. Fmoc-chemistry was used and the 19- or15-residue peptides were respectively coupled to keyhole limpethemocyanin (KLH, Sigma, St. Louis, Mo.) by reaction withN-maleimidobenzoyl-N-hydroxysuccinimide ester (MBS). Rabbits wereimmunized with the oligopeptide-KLH complex in complete Freund'sadjuvant. The resulting antisera were tested for antipeptide activity,e.g., by binding the peptide to plastic, blocking with 1% BSA, reactingwith rabbit antisera, washing, and reacting with radioiodinated, goatanti-rabbit IgG.

[0120] Western blotting was performed using normal human protein samples(Protein Medley) obtained from Clontech (about 36 μg of total proteins).Proteins were fractionated through 10% SDS-polyacrylamide gels, andtransferred to 0.45 mm nitrocellulose membranes. Membranes were blockedin Tris-buffered saline (TBS) with 0.05% Tween 20 and 1% BSA. AntiDPRP-1 or DPRP-2 specific antibodies were used as primary antibodies andwere diluted 1:5,000 in Tris-buffered saline with 0.05% Tween 20 (TBST)and the Alkaline Phosphatase (AP) conjugated goat anti-Rabbit IgG(Promega) was diluted 1:5,000 in the same buffer before use. Thepositive reaction was visualized by incubating the membrane in WesternBlue Stabilized Substrate (Promega) for AP until the bands of interesthave reached the desired intensity. DPRP-1 and DPRP-2 proteins weredetected in brain, muscles, kidney, prostate, testis and ovary tissues.DPRP-1 and DPRP-2 were synthesized as approximately 101 kDa and 100 kDaforms, respectively, which are in good agreement with the molecularmasses estimated from their primary structure as shown in Table 3. TABLE3 Predicted Molecular Weight, Number of potential N-linked glycosylationsites (Asn residues) and predicted pI values of DPRP-1, DPRP-2 andDPRP-3, based on sequence analysis using the method developed by Hoppand Woods, Proc. Nat. Acad. Sci. 78:3824-3828 (1981). M.W. (Da.) No. ofAsn pI DPRP1 101422 26 5.39 DPRP2  98263 27 6.01 DPRP3  90914 33 6.11

[0121] Several additional bands of similar molecular weight wereobserved. These are thought to be due to the presence ofpost-translational glycosylation of the proteins. Table 3 also shows thenumber of potential N-glycosylation sites for the DPRP proteins. Thepresence of glycosylated and unglcosylated forms of the proteins wasevaluated using tunicamycin, an inhibitor of the oligosaccharidesynthesis. It is evident that the smaller forms were unglycosylatedforms. The correlation between mRNA (Northern analysis) and proteinquantity (Western analysis) for DPRP-1 is shown in Table 4. TABLE 4Correlation of mRNA and protein expression of DPRP-1 in human tissuesHeart Brain Placenta Muscles Kidney Prostate Testis Ovary Northern +++++ + +++ ++ +++ ++++ + Western − ++++ − + ++ + +++ +++

EXAMPLE 4 Immunohistochemical Localization of DPRP Proteins in HumanTissues

[0122] Four-micron sections were prepared from a number of differentformalin-fixed, paraffin-embedded human tissues. Tissue sections weredeparaffined through 4 immersions in xylenes for 5 minutes, followed bya graded alcohol series to distilled water. Steam heat induced epitoperecovery (SHIER) was used with several different SHIER solutions withand without enzyme digestion tissue in two different concentrations(Ladner et al, Cancer Res.; 60, p 3493-3503, 2000). The treatments andantibody dilutions employed are outlined below.

[0123] 1. Blocking Reagent for 15 minutes (Normal Goat Serum)

[0124] 2. Primary Antibody for 25, 60 min or overnight incubation

[0125] 3. Secondary Antibody for 25 minutes (BiotinylatedGoat-anti-rabbit IgG)

[0126] 4. Endogenous Peroxidase Blocking for 3×1.5 minutes

[0127] 5. ABC (avidin-biotin complex)/Horse Radish Peroxidase for 25minutes

[0128] 6. DAB Chromogen for 3×5 minutes (Brown reaction product)

[0129] 7. Light Hematoxylin Counter Stain 1 minute

[0130] Positive controls were run to assure the detection chemistriesand antigen pretreatments were working appropriately. Rabbit IgG was runas a negative control. An avidin-biotin based tissue staining system wasused for the detection of the DPRP-1 antibody. Horseradish peroxide wasused as a reporter enzyme with DAB as chromogen. After staining, slideswere dehydrated through an alcohol series to absolute ethanol followedby xylene rinses. Slides were permanently coverslipped with glasscoverslips and permount. Digital images of representative staining,where positive staining was indicated by a dark brown chromogen (DAB-HRPreaction product), were captured using a video camera from Olympus.Hematoxylin counterstain provides a blue nuclear stain to assess celland tissue morphology.

[0131] DPRP-1 rabbit polyclonal antibody labels formalin-fixed,paraffin-embedded human tissues, including normal testis, prostateglands, endometrial glands, tonsils and pancreas. It was also present inendothelial cells of normal ovary, bladder and kidney. Staining waslocalized in the cytoplasm in epithelial and some stromal cells such asfibroblasts, endothelial cells and lymphocytes. Interestingly in normaltestis tested with DPRP-1 antibodies, there was distinctive expressionin Leydig cells and multinucleated macrophages found in interstitialtissue, which is the space surrounding the seminiferous tubules. TonsilB cells were stained with DPRP-1 antibody.

EXAMPLE 5 Mammalian and Insect Cell Expression of DPRP Proteins andPurification

[0132] Plasmid DNA of pcDNA-DPRP1, pcDNA-MycHis-DPRP1, pcDNA-DPRP-2 orpcDNA-MycHis-DPRP2 was transfected into PEAK (EdgeBioSystems,Gaithersburg Md., USA) or COS-1 (ATCC CRL-1650) using LipofectAmine(Life Technologies, Gaithersburg Md., USA) method recommended by themanufacturer. Transfected cells were maintained in DMEM with 5% FBS at37° C. with 5% CO₂ for 48 hours. Cells were then collected and used forrecombinant protein extraction. Cells were harvested 48 hours aftertransfection, homogenized and then spun at 18,000×g for 40 min. Thesupernata were collected as cytosolic fractions. This fraction wasloaded on TALON spin column (Clontech), and His-tagged proteins wereeluted with 50 mM PBS, 150 mM imidazole, pH 7. Recombinant proteins werethen detected by western blotting with anti-myc antibody and visualizedusing a ProtoBlot II AP system (Promega). Recombinant affinity purifiedfusions of the DPRP-1 and DPRP-2 were detected by western blot, andDPRP-1 and DPRP-2 were synthesized as 112 kDa and 109 kDa forms aspredicted.

[0133] Naturally occurring or recombinant DPRP proteins weresubstantially purified by immunoaffinity chromatography using antibodiesspecific for DPRP-1, DPRP-2 or DPRP-3. An immunoaffinity column wasconstructed by covalently coupling DPRP antibodies to an activatedchromatographic resin, such as CNBr-activated Sepharose (Pharmacia &Upjohn). After the coupling, the resin was blocked and washed accordingto the manufacturer's instructions.

[0134] Media or cell extracts containing DPRP proteins were passed overthe immunoaffinity column, and the column was washed under conditionsthat allow the preferential absorbance of DPRPs (e.g., high ionicstrength buffers in the presence of detergent). The column was elutedunder conditions that disrupt antibody/DPRP binding (e.g., a buffer ofpH 2-3 or a high concentration of a chaotrope, such as urea orthiocyanate ion), and purified DPRP was collected.

EXAMPLE 6 Enzymatic Activity of DPRP Proteins and Methods of Screeningfor Inhibitors

[0135] The kinetic properties of recombinant DPRP-1 and DPRP-2 weredetermined in a continuous fluorimetric assay. Buffer, pH andtemperature dependence optimization led to the following assayconditions: Enzyme assays were performed in 50 mM PBS, pH7.4 50 μl (50μg/ml) of purified enzymes were mixed with 1 μl of differentconcentration of Ala-Pro-AMC (Enzyme Systems). Plates were thenincubated at 37° C. for 30 min, and fluorescence was detected using aWallac 1420 Fluorimeter with λex40355 and λem535. The K_(m) values ofDPRP-1 and DPRP-2 were similar (208 and 161 μM respectively).

[0136] Further biochemical characterization reveals that DPRP-1 andDPRP-2 have similar profiles to DPPIV. The two purified proteases andDPPIV were preincubated with inhibitors at room temperature for 30 min.Substrate, Ala-Pro-AMC (100 μM), was then added, and the fluorescenceintensity was recorded as 60 readings during a 60 min period. Theirreversible serine protease inhibitor AEBSF was the only inhibitortested that showed strong inhibition of all three enzymes (Table 5).This confirms the structural and domain analysis prediction that theseproteins belong to the serine protease superfamily. TABLE 5 Inhibitionof DPRP-1 and DPRP-2 by Protease Inhibitors Residual activity InhibitorCon- (% of control) Inhibitor Property centration DPRP-1 DPRP-2 DPPIVAEBSF serine, 5 mM 29.6 23.9 21.1 irreversible Aprotinin serine, 5 μg/ml77.5 63.2 80.2 reversible Pepstatin aspartic, 2 μg/ml 97.3 95.0 93.5reversible DTT cysteine 2 mM 100.1 94.8 98.3 B- cysteine 100 mM 93.284.0 98.0 Mercaptoethonal EDTA metallo, 2 mM 91.5 86.0 93.5 reversibleLeupeptin serine, 50 μg/ml 91.1 90.4 90.7 reversible

[0137] In addition to Ala-Pro-AMC, additional substrates tested alsoconfirmed that DPRP-1 and DPRP-2 are dipeptidyl peptidases. The datawere derived by determining the fluorescence change following a30-minute incubation of the substrates (125 μM) with enzymes as apercentage of the fluorescence measured at Ala-Pro-AMC and Gly-Pro-AMCwere the only good substrates among those tested. TABLE 6 DPRP-1 andDPRP-2 are dipeptidyl peptidases. % Change in Fluorescence at 30 minutesSubstrate DPRP-1 DPRP-2 DPPIV Ala-Pro-AMC 239.0 127.5 379.0 Gly-Pro-AMC341.5 205.0 444.0 Ala-Pro-pNA 45.5 44.0 29.5 Pro-pNA −1 −2.5 0.0Gly-Arg-pNA −4.5 −0.5 0.0 Lys-Ala-pNA 2.5 0.5 0.5 Ala-Phe-Pro-pNA −4−0.5 2.0

[0138] Additional natural and non-natural amino acid di-, tri- andtetra-peptides were tested in order to find an optimal substrate fortesting each of the DPRP proteins that will also show reduced activitywhen incubated DPPIV.

[0139] The enzyme assay method described here is one of a number ofmethods that can be utilized to screen for peptide and non-peptideinhibitors of the DPRP enzymes. Libraries of tetrapeptide inhibitorswere tested to discover inhibitors of enzyme activity. Candidateinhibitors were prepared as 10-20 mM stock solutions in DMSO and storedat −20° C. Dilutions were made in assay buffer. Inhibition wasdetermined by comparing the changes in fluorescence of the inhibitedenzyme to the change in fluorescence of the control (vehicle) enzyme.100-(fl units of sample/fl units of control ×100) gives percentinhibition value. The percent inhibition and the inhibitor concentrationat which the enzyme was 50% inhibited (IC₅₀) was ascertained by plottingpercent inhibition vs. inhibitor concentration on the log scale. Asshown in FIG. 3, several tetrapeptides amides inhibited enzyme activity,wherein data are expressed as the % of activity in the presence ofvehicle (0.02% DMSO) alone. Compounds were added at 1 mM. Mostinteresting was the apparent differential activity of some tetrapeptidesfor DPRP-1 and DPRP-2, compared to DPPIV. While all three enzymes wereinhibited by Peptide-1, only DPRP-1 and DPRP-2 were significantlyinhibited by Peptide-4 and Peptide-5. This demonstrates that selectiveinhibition of the purified enzymes is achievable.

[0140] The assay described in this example can also be used to screenadditional synthetic or naturally occurring compound libraries,including macromolecules, for agents that either inhibit or enhance DPRPactivity. The DPRP-1 and DPRP-2 polypeptides to be used in the assay canbe obtained by, for example, in vitro translation, recombinantexpression (see Example 5) or biochemical procedures. Methods other thanthose described here can also be used to screen and identify compoundsthat inhibit DPRP-1, DPRP-2 or DPRP-3, which methods can include, forexample, binding assays such as ELISAs and RIAs.

EXAMPLE 7 Effect of DPRP Inhibitors on the Proliferation of Human CancerCells In Vitro

[0141] In an attempt to assess the effect that several inhibitors ofDPRP-1 and DPRP-2 activity may have on the proliferation of human cancercells, LNCap, PC3 and Du145, mouse testis line MLTC-1 and MDA-MB231breast cancer cells were plated (10⁴ per well) in 96-well tissue cultureplates and allowed to grow and attach for 24 hours at 37° C. in a CO₂incubator. Compounds at various dilutions (final dilutions: 0.1 nM-10μM) were then added to the wells for various incubation periods from 24hours to 96 hours, with fresh compound being replaced each day. Additionof the diluent DMSO alone served as the control. Following incubationwith these compounds in triplicate, proliferation of the cells wasdetermined using an XTT cell proliferation assay (Roche 1-465-015). Theplates were read at 490 and 650 nm 5 hours after the XTT mix was added.An increase in cell proliferation was observed with three of theinhibitors at concentrations equal to 0.1, 1, 10 and 100×IC₅₀, and theresults are shown in FIGS. 4A, 4B and 4C for PC3 cells.

[0142] Overall, the DPRPs are expressed in a wide variety of tissues ashas been demonstrated by mRNA amplification, western blotting andimmunohistochemistry. DPRP-1 was most abundant in the testis by Northernblot and western blot. The large number of expressed sequence tags(ESTs) from testis cDNA sources that are homologous to DPRP-1 alsoconfirms abundant expression of DPRP-1 in testis. Example 4 describesthe immunohistochemical localization of DPRP-1 protein in human testisusing a specific DPRP-1 antibody. DPRP-1 is strongly expressed inepitheloid Leydig cells, and Leydig cells are the primary source oftesticular androgens (male steroid hormones) in the mammalian male. Inthe interstitium of the testis, Leydig cells and macrophages are inclose association with “digitation” of Leydig cell process extendingonto macrophage surface. Multinucleated cells in close proximity to theLeydig cells were also stained with DPRP-1 antibody suggesting that theprotease was also expressed in macrophages, and macrophages in thetestis play an important role in the paracrine regulation of Leydigcells. Cytokines secreted by the testicular macrophages are mitogenic toLeydig cells and play an important role in the differentiation ofmesenchymal progenitor cell into mature Leydig cells. A clearerunderstanding of the proteins and pathways involved in the maturation ofthe testis is important for the discovery of new treatments forprecocious puberty. In addition, Leydig cells cause tumors such as sexcord-stromal tumors via sexual steroid production (predominantlytestosterone). Testosterone is associated with several neoplasia anddiseases such as breast carcinoma and uterine cancers, ovarian carcinomaand androgenic alopecia (hair loss). Further examination of thelocalization of DPRP proteins in other glands in the body (e.g. adrenalglands) that produce testosterone and other androgenic hormones arecurrently under investigation. The possible association of DPRP-1 withsteroid and polypeptide hormone biosynthetic pathways functions is beinginvestigated, and Example 7 is relevant to understanding the role ofDPRP proteins in prostate, testis and breast in vitro cell models.

[0143] Immunohistochemical analysis also localized DPRP-1 to endometrialglands in the uterus (see Example 4), pancreatic acini, glomeruli of thekidney, plasma cells in the bladder, a subset of B-cells in the tonsils,columnar epithelial cells of the prostate and poorly differentiatedprostate squamous metaplasia, Gleason grade 4 prostatic carcinoma, andhyperplastic glands in benign prostatic hyperplasia. Positive stainingin breast carcinoma, as well as in seminoma and prostate squamousmetaplasia, suggests a general association of DPRP-1 withhormone-sensitive tissues, particularly in cells that become poorlydifferentiated. The presence of the DPRP-1 in specialized epithelialcells and in inflammatory plasma cells (lymphocytes) is also ofinterest. Inflammatory breast carcinoma has an abundance of infiltratinglymphocytes and an overall bad prognosis. DPRP-1 and other DPRP proteinsappear in medullary carcinomas that typically have a constantinfiltrating lymphoplasmacytic component at the periphery of the tumor,which is thought to represent a reaction of the host tissues to theneoplasm. Most of the lymphocytes are T Cells, and most of the plasmacells are of the IgG-producing type. Several antigens are abundant on Bcells, a subgroup of breast-cancer cells, and other epithelial cancercells, and these antigens are targets for a new class of therapeuticmonoclonal antibodies with some notable success having been achievedwith a humanized monoclonal antibody against the B-cell-specific antigenCD20. Accordingly, monoclonal antibodies to DPRP proteins are felt to beuseful to diagnose and treat diseases in which they are involved,including cancer.

[0144] The expression of DPRP-1 in specialized epithelial cells of anumber of tissues suggests that DPRP-1 and other DPRP proteins may beinvolved in growth and differentiation thereof. Testing using inhibitorsdescribed in Example 6 in in vitro models of prostate and testis cancer(Example 7) showed that DPRP-1/DPRP-2 inhibitors caused a 50-60%increase in proliferation of PC3 cells at nM concentrations as shown inFIGS. 4A-4C.

[0145] Although the invention has been described in accordance with itspreferred embodiments, which constitute the best mode presently known tothe inventors, it should be understood that changes and modifications aswould be obvious to those skilled in this art may be made withoutdeparting from its scope which is set forth in the claims appendedhereto. For example, although the disclosure focuses on DPRP-1 andDPRP-2 in certain instances, DPRP-3 and its fragments are considered tobe similarly useful, as are nucleic acids encoding same. The disclosuresof all patents hereinbefore set forth are expressly incorporated hereinby reference. Particular features of the invention are emphasized in theclaims that follow.

Sequence Listing Summary

[0146] SEQ ID.

[0147] 1. DPRP1 a.a sequence

[0148] 2. DPRP1 DNA sequence

[0149] 3. DPRP2 a.a. sequence

[0150] 4. DPRP2 DNA sequence

[0151] 5. DPRP-3 a.a. sequence

[0152] 6. DPRP-3 DNA sequence

[0153] 7. DPRP-1 transcript 0 a.a.. sequence

[0154] 8. DPRP-1 transcript 0 DNA sequence

[0155] 9. DPRP-1 transcript 1 a.a. sequence

[0156] 10. DPRP-1 transcript 1 DNA sequence

[0157] 11. DPRP-1 transcript 2 a.a. sequence

[0158] 12. DPRP-1 transcript 2 DNA sequence

[0159] 13. DPRP-1 transcript 3 a.a. sequence

[0160] 14. DPRP-1 transcript 3 DNA sequence

[0161] 15. DPRP-1 transcript 4 a.a. sequence

[0162] 16. DPRP-1 transcript 4 DNA sequence

[0163] 17. DPRP-1 transcript 5 a.a. sequence

[0164] 18. DPRP-1 transcript 5 DNA sequence

[0165] 19. DPRP-1 transcript 6 a.a. sequence

[0166] 20. DPRP-1 transcript 6 DNA sequence

[0167] 21. DPRP-1 transcript 7 a.a. sequence

[0168] 22. DPRP-1 transcript 7 DNA sequence

[0169] 23. DPRP-2 transcript 0 a.a. sequence

[0170] 24. DPRP-2 transcript 0 DNA sequence

[0171] 25. DPRP-2 transcript 1 a.a. sequence

[0172] 26. DPRP-2 transcript 1 DNA sequence

[0173] 27. DPRP-2 transcript 2 a.a. sequence

[0174] 28. DPRP-2 transcript 2 DNA sequence

[0175] 29. DPRP-2 transcript 3 a.a. sequence

[0176] 30. DPRP-2 transcript 3 DNA sequence

[0177] 31. DPRP-2 transcript 4 a.a. sequence

[0178] 32. DPRP-2 transcript 4 DNA sequence

[0179] 33. DPRP-2 transcript 5 a.a. sequence

[0180] 34. DPRP-2 transcript 5 DNA sequence

[0181] 35. DPRP-2 transcript 6 a.a. sequence

[0182] 36. DPRP-2 transcript 6 DNA sequence

[0183] 37. DPRP-2 transcript 7 a.a. sequence

[0184] 38. DPRP-2 transcript 7 DNA sequence

[0185] 39. DPRP-2 transcript 8 a.a. sequence

[0186] 40. DPRP-2 transcript 8 DNA sequence

[0187] 41. DPRP-3 transcript 0 a.a. sequence

[0188] 42. DPRP-3 transcript 0 DNA. Sequence

[0189] 43. DPRP-3 transcript 1 a.a. sequence

[0190] 44. DPRP-3 transcript 1 DNA sequence

[0191] 45. DPRP1 forward primer used for cloning

[0192] 46. DPRP1 reverse primer used for cloning full length gene

[0193] 47. DPRP1 reverse primer used for cloning fusion gene

[0194] 48. DPRP1 forward primer used for expression profiling

[0195] 49. DPRP1 reverse primer used for expression profiling

[0196] 50. DPRP2 forward primer used for cloning

[0197] 51. DPRP2 reverse primer used for cloning full length gene

[0198] 52. DPRP2 reverse primer used for cloning fusion gene

[0199] 53. DPRP2 forward primer used for expression profiling

[0200] 54. DPRP2 reverse primer used for expression profiling

[0201] 55. DPRP3 forward primer used for cloning

[0202] 56. DPRP3 reverse primer used for cloning full length gene

[0203] 57. DPRP3 forward primer used for cloning fusion gene

[0204] 58. DPRP3 reverse primer used for cloning fusion gene

[0205] 59. DPRP1 peptide antigen sequences

[0206] 60. DPRP2 peptide antigen sequences

[0207] 61. DPRP3 peptide antigen sequences

1 61 1 882 PRT Homo sapiens 1 Met Ala Ala Ala Met Glu Thr Glu Gln LeuGly Val Glu Ile Phe Glu 1 5 10 15 Thr Ala Asp Cys Glu Glu Asn Ile GluSer Gln Asp Arg Pro Lys Leu 20 25 30 Glu Pro Phe Tyr Val Glu Arg Tyr SerTrp Ser Gln Leu Lys Lys Leu 35 40 45 Leu Ala Asp Thr Arg Lys Tyr His GlyTyr Met Met Ala Lys Ala Pro 50 55 60 His Asp Phe Met Phe Val Lys Arg AsnAsp Pro Asp Gly Pro His Ser 65 70 75 80 Asp Arg Ile Tyr Tyr Leu Ala MetSer Gly Glu Asn Arg Glu Asn Thr 85 90 95 Leu Phe Tyr Ser Glu Ile Pro LysThr Ile Asn Arg Ala Ala Val Leu 100 105 110 Met Leu Ser Trp Lys Pro LeuLeu Asp Leu Phe Gln Ala Thr Leu Asp 115 120 125 Tyr Gly Met Tyr Ser ArgGlu Glu Glu Leu Leu Arg Glu Arg Lys Arg 130 135 140 Ile Gly Thr Val GlyIle Ala Ser Tyr Asp Tyr His Gln Gly Ser Gly 145 150 155 160 Thr Phe LeuPhe Gln Ala Gly Ser Gly Ile Tyr His Val Lys Asp Gly 165 170 175 Gly ProGln Gly Phe Thr Gln Gln Pro Leu Arg Pro Asn Leu Val Glu 180 185 190 ThrSer Cys Pro Asn Ile Arg Met Asp Pro Lys Leu Cys Pro Ala Asp 195 200 205Pro Asp Trp Ile Ala Phe Ile His Ser Asn Asp Ile Trp Ile Ser Asn 210 215220 Ile Val Thr Arg Glu Glu Arg Arg Leu Thr Tyr Val His Asn Glu Leu 225230 235 240 Ala Asn Met Glu Glu Asp Ala Arg Ser Ala Gly Val Ala Thr PheVal 245 250 255 Leu Gln Glu Glu Phe Asp Arg Tyr Ser Gly Tyr Trp Trp CysPro Lys 260 265 270 Ala Glu Thr Thr Pro Ser Gly Gly Lys Ile Leu Arg IleLeu Tyr Glu 275 280 285 Glu Asn Asp Glu Ser Glu Val Glu Ile Ile His ValThr Ser Pro Met 290 295 300 Leu Glu Thr Arg Arg Ala Asp Ser Phe Arg TyrPro Lys Thr Gly Thr 305 310 315 320 Ala Asn Pro Lys Val Thr Phe Lys MetSer Glu Ile Met Ile Asp Ala 325 330 335 Glu Gly Arg Ile Ile Asp Val IleAsp Lys Glu Leu Ile Gln Pro Phe 340 345 350 Glu Ile Leu Phe Glu Gly ValGlu Tyr Ile Ala Arg Ala Gly Trp Thr 355 360 365 Pro Glu Gly Lys Tyr AlaTrp Ser Ile Leu Leu Asp Arg Ser Gln Thr 370 375 380 Arg Leu Gln Ile ValLeu Ile Ser Pro Glu Leu Phe Ile Pro Val Glu 385 390 395 400 Asp Asp ValMet Glu Arg Gln Arg Leu Ile Glu Ser Val Pro Asp Ser 405 410 415 Val ThrPro Leu Ile Ile Tyr Glu Glu Thr Thr Asp Ile Trp Ile Asn 420 425 430 IleHis Asp Ile Phe His Val Phe Pro Gln Ser His Glu Glu Glu Ile 435 440 445Glu Phe Ile Phe Ala Ser Glu Cys Lys Thr Gly Phe Arg His Leu Tyr 450 455460 Lys Ile Thr Ser Ile Leu Lys Glu Ser Lys Tyr Lys Arg Ser Ser Gly 465470 475 480 Gly Leu Pro Ala Pro Ser Asp Phe Lys Cys Pro Ile Lys Glu GluIle 485 490 495 Ala Ile Thr Ser Gly Glu Trp Glu Val Leu Gly Arg His GlySer Asn 500 505 510 Ile Gln Val Asp Glu Val Arg Arg Leu Val Tyr Phe GluGly Thr Lys 515 520 525 Asp Ser Pro Leu Glu His His Leu Tyr Val Val SerTyr Val Asn Pro 530 535 540 Gly Glu Val Thr Arg Leu Thr Asp Arg Gly TyrSer His Ser Cys Cys 545 550 555 560 Ile Ser Gln His Cys Asp Phe Phe IleSer Lys Tyr Ser Asn Gln Lys 565 570 575 Asn Pro His Cys Val Ser Leu TyrLys Leu Ser Ser Pro Glu Asp Asp 580 585 590 Pro Thr Cys Lys Thr Lys GluPhe Trp Ala Thr Ile Leu Asp Ser Ala 595 600 605 Gly Pro Leu Pro Asp TyrThr Pro Pro Glu Ile Phe Ser Phe Glu Ser 610 615 620 Thr Thr Gly Phe ThrLeu Tyr Gly Met Leu Tyr Lys Pro His Asp Leu 625 630 635 640 Gln Pro GlyLys Lys Tyr Pro Thr Val Leu Phe Ile Tyr Gly Gly Pro 645 650 655 Gln ValGln Leu Val Asn Asn Arg Phe Lys Gly Val Lys Tyr Phe Arg 660 665 670 LeuAsn Thr Leu Ala Ser Leu Gly Tyr Val Val Val Val Ile Asp Asn 675 680 685Arg Gly Ser Cys His Arg Gly Leu Lys Phe Glu Gly Ala Phe Lys Tyr 690 695700 Lys Met Gly Gln Ile Glu Ile Asp Asp Gln Val Glu Gly Leu Gln Tyr 705710 715 720 Leu Ala Ser Arg Tyr Asp Phe Ile Asp Leu Asp Arg Val Gly IleHis 725 730 735 Gly Trp Ser Tyr Gly Gly Tyr Leu Ser Leu Met Ala Leu MetGln Arg 740 745 750 Ser Asp Ile Phe Arg Val Ala Ile Ala Gly Ala Pro ValThr Leu Trp 755 760 765 Ile Phe Tyr Asp Thr Gly Tyr Thr Glu Arg Tyr MetGly His Pro Asp 770 775 780 Gln Asn Glu Gln Gly Tyr Tyr Leu Gly Ser ValAla Met Gln Ala Glu 785 790 795 800 Lys Phe Pro Ser Glu Pro Asn Arg LeuLeu Leu Leu His Gly Phe Leu 805 810 815 Asp Glu Asn Val His Phe Ala HisThr Ser Ile Leu Leu Ser Phe Leu 820 825 830 Val Arg Ala Gly Lys Pro TyrAsp Leu Gln Ile Tyr Pro Gln Glu Arg 835 840 845 His Ser Ile Arg Val ProGlu Ser Gly Glu His Tyr Glu Leu His Leu 850 855 860 Leu His Tyr Leu GlnGlu Asn Leu Gly Ser Arg Ile Ala Ala Leu Lys 865 870 875 880 Val Ile 22671 DNA Homo sapiens 2 cggtaccatg gcagcagcaa tggaaacaga acagctgggtgttgagatat ttgaaactgc 60 ggactgtgag gagaatattg aatcacagga tcggcctaaattggagcctt tttatgttga 120 gcggtattcc tggagtcagc ttaaaaagct gcttgccgataccagaaaat atcatggcta 180 catgatggct aaggcaccac atgatttcat gtttgtgaagaggaatgatc cagatggacc 240 tcattcagac agaatctatt accttgccat gtctggtgagaacagagaaa atacactgtt 300 ttattctgaa attcccaaaa ctatcaatag agcagcagtcttaatgctct cttggaagcc 360 tcttttggat ctttttcagg caacactgga ctatggaatgtattctcgag aagaagaact 420 attaagagaa agaaaacgca ttggaacagt cggaattgcttcttacgatt atcaccaagg 480 aagtggaaca tttctgtttc aagccggtag tggaatttatcacgtaaaag atggagggcc 540 acaaggattt acgcaacaac ctttaaggcc caatctagtggaaactagtt gtcccaacat 600 acggatggat ccaaaattat gccctgctga tccagactggattgctttta tacatagcaa 660 cgatatttgg atatctaaca tcgtaaccag agaagaaaggagactcactt atgtgcacaa 720 tgagctagcc aacatggaag aagatgccag atcagctggagtcgctacct ttgttctcca 780 agaagaattt gatagatatt ctggctattg gtggtgtccaaaagctgaaa caactcccag 840 tggtggtaaa attcttagaa ttctatatga agaaaatgatgaatctgagg tggaaattat 900 tcatgttaca tcccctatgt tggaaacaag gagggcagattcattccgtt atcctaaaac 960 aggtacagca aatcctaaag tcacttttaa gatgtcagaaataatgattg atgctgaagg 1020 aaggatcata gatgtcatag ataaggaact aattcaaccttttgagattc tatttgaagg 1080 agttgaatat attgccagag ctggatggac tcctgagggaaaatatgctt ggtccatcct 1140 actagatcgc tcccagactc gcctgcagat agtgttgatctcacctgaat tatttatccc 1200 agtagaagat gatgttatgg aaaggcagag actcattgagtcagtgcctg attctgtgac 1260 gccactaatt atctatgaag aaacaacaga catctggataaatatccatg acatctttca 1320 tgtttttccc caaagtcacg aagaggaaat tgagtttatttttgcctctg aatgcaaaac 1380 aggtttccgt catttataca aaattacatc tattttaaaggaaagcaaat ataaacgatc 1440 cagtggtggg ctgcctgctc caagtgattt caagtgtcctatcaaagagg agatagcaat 1500 taccagtggt gaatgggaag ttcttggccg gcatggatctaatatccaag ttgatgaagt 1560 cagaaggctg gtatattttg aaggcaccaa agactcccctttagagcatc acctgtacgt 1620 agtcagttac gtaaatcctg gagaggtgac aaggctgactgaccgtggct actcacattc 1680 ttgctgcatc agtcagcact gtgacttctt tataagtaagtatagtaacc agaagaatcc 1740 acactgtgtg tccctttaca agctatcaag tcctgaagatgacccaactt gcaaaacaaa 1800 ggaattttgg gccaccattt tggattcagc aggtcctcttcctgactata ctcctccaga 1860 aattttctct tttgaaagta ctactggatt tacattgtatgggatgctct acaagcctca 1920 tgatctacag cctggaaaga aatatcctac tgtgctgttcatatatggtg gtcctcaggt 1980 gcagttggtg aataatcgat ttaaaggagt caagtatttccgcttgaata ccctagcctc 2040 tctaggttat gtggttgtag tgatagacaa caggggatcctgtcaccgag ggcttaaatt 2100 tgaaggcgcc tttaaatata aaatgggtca aatagaaattgacgatcagg tggaaggact 2160 ccaatatcta gcttctcgat atgatttcat tgacttagatcgtgtgggca tccacggctg 2220 gtcctatgga ggatacctct ccctgatggc attaatgcagaggtcagata tcttcagggt 2280 tgctattgct ggggccccag tcactctgtg gatcttctatgatacaggat acacggaacg 2340 ttatatgggt caccctgacc agaatgaaca gggctattacttaggatctg tggccatgca 2400 agcagaaaag ttcccctctg aaccaaatcg tttactgctcttacatggtt tcctggatga 2460 gaatgtccat tttgcacata ccagtatatt actgagttttttagtgaggg ctggaaagcc 2520 atatgattta cagatctatc ctcaggagag acacagcataagagttcctg aatcgggaga 2580 acattatgaa ctgcatcttt tgcactacct tcaagaaaaccttggatcac gtattgctgc 2640 tctaaaagtg atatgagcgg ccgcgagctc c 2671 3 863PRT Homo sapiens 3 Met Ala Thr Thr Gly Thr Pro Thr Ala Asp Arg Gly AspAla Ala Ala 1 5 10 15 Thr Asp Asp Pro Ala Ala Arg Phe Gln Val Gln LysHis Ser Trp Asp 20 25 30 Gly Leu Arg Ser Ile Ile His Gly Ser Arg Lys TyrSer Gly Leu Ile 35 40 45 Val Asn Lys Ala Pro His Asp Phe Gln Phe Val GlnLys Thr Asp Glu 50 55 60 Ser Gly Pro His Ser His Arg Leu Tyr Tyr Leu GlyMet Pro Tyr Gly 65 70 75 80 Ser Arg Glu Asn Ser Leu Leu Tyr Ser Glu IlePro Lys Lys Val Arg 85 90 95 Lys Glu Ala Leu Leu Leu Leu Ser Trp Lys GlnMet Leu Asp His Phe 100 105 110 Gln Ala Thr Pro His His Gly Val Tyr SerArg Glu Glu Glu Leu Leu 115 120 125 Arg Glu Arg Lys Arg Leu Gly Val PheGly Ile Thr Ser Tyr Asp Phe 130 135 140 His Ser Glu Ser Gly Leu Phe LeuPhe Gln Ala Ser Asn Ser Leu Phe 145 150 155 160 His Cys Arg Asp Gly GlyLys Asn Gly Phe Met Val Ser Pro Met Lys 165 170 175 Pro Leu Glu Ile LysThr Gln Cys Ser Gly Pro Arg Met Asp Pro Lys 180 185 190 Ile Cys Pro AlaAsp Pro Ala Phe Phe Ser Phe Ile Asn Asn Ser Asp 195 200 205 Leu Trp ValAla Asn Ile Glu Thr Gly Glu Glu Arg Arg Leu Thr Phe 210 215 220 Cys HisGln Gly Leu Ser Asn Val Leu Asp Asp Pro Lys Ser Ala Gly 225 230 235 240Val Ala Thr Phe Val Ile Gln Glu Glu Phe Asp Arg Phe Thr Gly Tyr 245 250255 Trp Trp Cys Pro Thr Ala Ser Trp Glu Gly Ser Glu Gly Leu Lys Thr 260265 270 Leu Arg Ile Leu Tyr Glu Glu Val Asp Glu Ser Glu Val Glu Val Ile275 280 285 His Val Pro Ser Pro Ala Leu Glu Glu Arg Lys Thr Asp Ser TyrArg 290 295 300 Tyr Pro Arg Thr Gly Ser Lys Asn Pro Lys Ile Ala Leu LysLeu Ala 305 310 315 320 Glu Phe Gln Thr Asp Ser Gln Gly Lys Ile Val SerThr Gln Glu Lys 325 330 335 Glu Leu Val Gln Pro Phe Ser Ser Leu Phe ProLys Val Glu Tyr Ile 340 345 350 Ala Arg Ala Gly Trp Thr Arg Asp Gly LysTyr Ala Trp Ala Met Phe 355 360 365 Leu Asp Arg Pro Gln Gln Trp Leu GlnLeu Val Leu Leu Pro Pro Ala 370 375 380 Leu Phe Ile Pro Ser Thr Glu AsnGlu Glu Gln Arg Leu Ala Ser Ala 385 390 395 400 Arg Ala Val Pro Arg AsnVal Gln Pro Tyr Val Val Tyr Glu Glu Val 405 410 415 Thr Asn Val Trp IleAsn Val His Asp Ile Phe Tyr Pro Phe Pro Gln 420 425 430 Ser Glu Gly GluAsp Glu Leu Cys Phe Leu Arg Ala Asn Glu Cys Lys 435 440 445 Thr Gly PheCys His Leu Tyr Lys Val Thr Ala Val Leu Lys Ser Gln 450 455 460 Gly TyrAsp Trp Ser Glu Pro Phe Ser Pro Gly Glu Asp Glu Phe Lys 465 470 475 480Cys Pro Ile Lys Glu Glu Ile Ala Leu Thr Ser Gly Glu Trp Glu Val 485 490495 Leu Ala Arg His Gly Ser Lys Ile Trp Val Asn Glu Glu Thr Lys Leu 500505 510 Val Tyr Phe Gln Gly Thr Lys Asp Thr Pro Leu Glu His His Leu Tyr515 520 525 Val Val Ser Tyr Glu Ala Ala Gly Glu Ile Val Arg Leu Thr ThrPro 530 535 540 Gly Phe Ser His Ser Cys Ser Met Ser Gln Asn Phe Asp MetPhe Val 545 550 555 560 Ser His Tyr Ser Ser Val Ser Thr Pro Pro Cys ValHis Val Tyr Lys 565 570 575 Leu Ser Gly Pro Asp Asp Asp Pro Leu His LysGln Pro Arg Phe Trp 580 585 590 Ala Ser Met Met Glu Ala Ala Ser Cys ProPro Asp Tyr Val Pro Pro 595 600 605 Glu Ile Phe His Phe His Thr Arg SerAsp Val Arg Leu Tyr Gly Met 610 615 620 Ile Tyr Lys Pro His Ala Leu GlnPro Gly Lys Lys His Pro Thr Val 625 630 635 640 Leu Phe Val Tyr Gly GlyPro Gln Val Gln Leu Val Asn Asn Ser Phe 645 650 655 Lys Gly Ile Lys TyrLeu Arg Leu Asn Thr Leu Ala Ser Leu Gly Tyr 660 665 670 Ala Val Val ValIle Asp Gly Arg Gly Ser Cys Gln Arg Gly Leu Arg 675 680 685 Phe Glu GlyAla Leu Lys Asn Gln Met Gly Gln Val Glu Ile Glu Asp 690 695 700 Gln ValGlu Gly Leu Gln Phe Val Ala Glu Lys Tyr Gly Phe Ile Asp 705 710 715 720Leu Ser Arg Val Ala Ile His Gly Trp Ser Tyr Gly Gly Phe Leu Ser 725 730735 Leu Met Gly Leu Ile His Lys Pro Gln Val Phe Lys Val Ala Ile Ala 740745 750 Gly Ala Pro Val Thr Val Trp Met Ala Tyr Asp Thr Gly Tyr Thr Glu755 760 765 Arg Tyr Met Asp Val Pro Glu Asn Asn Gln His Gly Tyr Glu AlaGly 770 775 780 Ser Val Ala Leu His Val Glu Lys Leu Pro Asn Glu Pro AsnArg Leu 785 790 795 800 Leu Ile Leu His Gly Phe Leu Asp Glu Asn Val HisPhe Phe His Thr 805 810 815 Asn Phe Leu Val Ser Gln Leu Ile Arg Ala GlyLys Pro Tyr Gln Leu 820 825 830 Gln Ile Tyr Pro Asn Glu Arg His Ser IleArg Cys Pro Glu Ser Gly 835 840 845 Glu His Tyr Glu Val Thr Leu Leu HisPhe Leu Gln Glu Tyr Leu 850 855 860 4 2617 DNA Homo sapiens 4 caagcttaccatggccacca ccgggacccc aacggccgac cgaggcgacg cagccgccac 60 agatgacccggccgcccgct tccaggtgca gaagcactcg tgggacgggc tccggagcat 120 catccacggcagccgcaagt actcgggcct cattgtcaac aaggcgcccc acgacttcca 180 gtttgtgcagaagacggatg agtctgggcc ccactcccac cgcctctact acctgggaat 240 gccatatggcagccgagaga actccctcct ctactctgag attcccaaga aggtccggaa 300 agaggctctgctgctcctgt cctggaagca gatgctggat catttccagg ccacgcccca 360 ccatggggtctactctcggg aggaggagct gctgagggag cggaaacgcc tgggggtctt 420 cggcatcacctcctacgact tccacagcga gagtggcctc ttcctcttcc aggccagcaa 480 cagcctcttccactgtcgcg acggcggcaa gaacggcttc atggtgtccc ctatgaaacc 540 gctggaaatcaagacccagt gctcagggcc ccggatggac cccaaaatct gccctgccga 600 ccctgccttcttctccttca tcaataacag cgacctgtgg gtggccaaca tcgagacagg 660 cgaggagcggcggctgacct tctgccacca aggtttatcc aatgtcctgg atgaccccaa 720 gtctgcgggtgtggccacct tcgtcataca ggaagagttc gaccgcttca ctgggtactg 780 gtggtgccccacagcctcct gggaaggttc agagggcctc aagacgctgc gaatcctgta 840 tgaggaagtcgatgagtccg aggtggaggt cattcacgtc ccctctcctg cgctagaaga 900 aaggaagacggactcgtatc ggtaccccag gacaggcagc aagaatccca agattgcctt 960 gaaactggctgagttccaga ctgacagcca gggcaagatc gtctcgaccc aggagaagga 1020 gctggtgcagcccttcagct cgctgttccc gaaggtggag tacatcgcca gggccgggtg 1080 gacccgggatggcaaatacg cctgggccat gttcctggac cggccccagc agtggctcca 1140 gctcgtcctcctccccccgg ccctgttcat cccgagcaca gagaatgagg agcagcggct 1200 agcctctgccagagctgtcc ccaggaatgt ccagccgtat gtggtgtacg aggaggtcac 1260 caacgtctggatcaatgttc atgacatctt ctatcccttc ccccaatcag agggagagga 1320 cgagctctgctttctccgcg ccaatgaatg caagaccggc ttctgccatt tgtacaaagt 1380 caccgccgttttaaaatccc agggctacga ttggagtgag cccttcagcc ccggggaaga 1440 tgaatttaagtgccccatta aggaagagat tgctctgacc agcggtgaat gggaggtttt 1500 ggcgaggcacggctccaaga tctgggtcaa tgaggagacc aagctggtgt acttccaggg 1560 caccaaggacacgccgctgg agcaccacct ctacgtggtc agctatgagg cggccggcga 1620 gatcgtacgcctcaccacgc ccggcttctc ccatagctgc tccatgagcc agaacttcga 1680 catgttcgtcagccactaca gcagcgtgag cacgccgccc tgcgtgcacg tctacaagct 1740 gagcggccccgacgacgacc ccctgcacaa gcagccccgc ttctgggcta gcatgatgga 1800 ggcagccagctgccccccgg attatgttcc tccagagatc ttccatttcc acacgcgctc 1860 ggatgtgcggctctacggca tgatctacaa gccccacgcc ttgcagccag ggaagaagca 1920 ccccaccgtcctctttgtat atggaggccc ccaggtgcag ctggtgaata actccttcaa 1980 aggcatcaagtacttgcggc tcaacacact ggcctccctg ggctacgccg tggttgtgat 2040 tgacggcaggggctcctgtc agcgagggct tcggttcgaa ggggccctga aaaaccaaat 2100 gggccaggtggagatcgagg accaggtgga gggcctgcag ttcgtggccg agaagtatgg 2160 cttcatcgacctgagccgag ttgccatcca tggctggtcc tacgggggct tcctctcgct 2220 catggggctaatccacaagc cccaggtgtt caaggtggcc atcgcgggtg ccccggtcac 2280 cgtctggatggcctacgaca cagggtacac tgagcgctac atggacgtcc ctgagaacaa 2340 ccagcacggctatgaggcgg gttccgtggc cctgcacgtg gagaagctgc ccaatgagcc 2400 caaccgcttgcttatcctcc acggcttcct ggacgaaaac gtgcactttt tccacacaaa 2460 cttcctcgtctcccaactga tccgagcagg gaaaccttac cagctccaga tctaccccaa 2520 cgagagacacagtattcgct gccccgagtc gggcgagcac tatgaagtca cgttgctgca 2580 ctttctacaggaatacctct gagcggccgc ggatccg 2617 5 796 PRT Homo sapiens 5 Met Asn GlnThr Ala Ser Val Ser His His Ile Lys Cys Gln Pro Ser 1 5 10 15 Lys ThrIle Lys Glu Leu Gly Ser Asn Ser Pro Pro Gln Arg Asn Trp 20 25 30 Lys GlyIle Ala Ile Ala Leu Leu Val Ile Leu Val Val Cys Ser Leu 35 40 45 Ile ThrMet Ser Val Ile Leu Leu Ser Pro Asp Glu Leu Thr Asn Ser 50 55 60 Ser GluThr Arg Leu Ser Leu Glu Asp Leu Phe Arg Lys Asp Phe Val 65 70 75 80 LeuHis Asp Pro Glu Ala Arg Trp Ile Asn Asp Thr Asp Val Val Tyr 85 90 95 LysSer Glu Asn Gly His Val Ile Lys Leu Asn Ile Glu Thr Asn Ala 100 105 110Thr Thr Leu Leu Leu Glu Asn Thr Thr Phe Val Thr Phe Lys Ala Ser 115 120125 Arg His Ser Val Ser Pro Asp Leu Lys Tyr Val Leu Leu Ala Tyr Asp 130135 140 Val Lys Gln Ile Phe His Tyr Ser Tyr Thr Ala Ser Tyr Val Ile Tyr145 150 155 160 Asn Ile His Thr Arg Glu Val Trp Glu Leu Asn Pro Pro GluVal Glu 165 170 175 Asp Ser Val Leu Gln Tyr Ala Ala Trp Gly Val Gln GlyGln Gln Leu 180 185 190 Ile Tyr Ile Phe Glu Asn Asn Ile Tyr Tyr Gln ProAsp Ile Lys Ser 195 200 205 Ser Ser Leu Arg Leu Thr Ser Ser Gly Lys GluGlu Ile Ile Phe Asn 210 215 220 Gly Ile Ala Asp Trp Leu Tyr Glu Glu GluLeu Leu His Ser His Ile 225 230 235 240 Ala His Trp Trp Ser Pro Asp GlyGlu Arg Leu Ala Phe Leu Met Ile 245 250 255 Asn Asp Ser Leu Val Pro ThrMet Val Ile Pro Arg Phe Thr Gly Ala 260 265 270 Leu Tyr Pro Lys Gly LysGln Tyr Pro Tyr Pro Lys Ala Gly Gln Val 275 280 285 Asn Pro Thr Ile LysLeu Tyr Val Val Asn Leu Tyr Gly Pro Thr His 290 295 300 Thr Leu Glu LeuMet Pro Pro Asp Ser Phe Lys Ser Arg Glu Tyr Tyr 305 310 315 320 Ile ThrMet Val Lys Trp Val Ser Asn Thr Lys Thr Val Val Arg Trp 325 330 335 LeuAsn Arg Pro Gln Asn Ile Ser Ile Leu Thr Val Cys Glu Thr Thr 340 345 350Thr Gly Ala Cys Ser Lys Lys Tyr Glu Met Thr Ser Asp Thr Trp Leu 355 360365 Ser Gln Gln Asn Glu Glu Pro Val Phe Ser Arg Asp Gly Ser Lys Phe 370375 380 Phe Met Thr Val Pro Val Lys Gln Gly Gly Arg Gly Glu Phe His His385 390 395 400 Ile Ala Met Phe Leu Ile Gln Ser Lys Ser Glu Gln Ile ThrVal Arg 405 410 415 His Leu Thr Ser Gly Asn Trp Glu Val Ile Lys Ile LeuAla Tyr Asp 420 425 430 Glu Thr Thr Gln Lys Ile Tyr Phe Leu Ser Thr GluSer Ser Pro Arg 435 440 445 Gly Arg Gln Leu Tyr Ser Ala Ser Thr Glu GlyLeu Leu Asn Arg Gln 450 455 460 Cys Ile Ser Cys Asn Phe Met Lys Glu GlnCys Thr Tyr Phe Asp Ala 465 470 475 480 Ser Phe Ser Pro Met Asn Gln HisPhe Leu Leu Phe Cys Glu Gly Pro 485 490 495 Arg Val Pro Val Val Ser LeuHis Ser Thr Asp Asn Pro Ala Lys Tyr 500 505 510 Phe Ile Leu Glu Ser AsnSer Met Leu Lys Glu Ala Ile Leu Lys Lys 515 520 525 Lys Ile Gly Lys ProGlu Ile Lys Ile Leu His Ile Asp Asp Tyr Glu 530 535 540 Leu Pro Leu GlnLeu Ser Leu Pro Lys Asp Phe Met Asp Arg Asn Gln 545 550 555 560 Tyr AlaLeu Leu Leu Ile Met Asp Glu Glu Pro Gly Gly Gln Leu Val 565 570 575 ThrAsp Lys Phe His Ile Asp Trp Asp Ser Val Leu Ile Asp Met Asp 580 585 590Asn Val Ile Val Ala Arg Phe Asp Gly Arg Gly Ser Gly Phe Gln Gly 595 600605 Leu Lys Ile Leu Gln Glu Ile His Arg Arg Leu Gly Ser Val Glu Val 610615 620 Lys Asp Gln Ile Thr Ala Val Lys Phe Leu Leu Lys Leu Pro Tyr Ile625 630 635 640 Asp Ser Lys Arg Leu Ser Ile Phe Gly Lys Gly Tyr Gly GlyTyr Ile 645 650 655 Ala Ser Met Ile Leu Lys Ser Asp Glu Lys Leu Phe LysCys Gly Ser 660 665 670 Val Val Ala Pro Ile Thr Asp Leu Lys Leu Tyr AlaSer Ala Phe Ser 675 680 685 Glu Arg Tyr Leu Gly Met Pro Ser Lys Glu GluSer Thr Tyr Gln Ala 690 695 700 Ala Ser Val Leu His Asn Val His Gly LeuLys Glu Glu Asn Ile Leu 705 710 715 720 Ile Ile His Gly Thr Ala Asp ThrLys Val His Phe Gln His Ser Ala 725 730 735 Glu Leu Ile Lys His Leu IleLys Ala Gly Val Asn Tyr Thr Met Gln 740 745 750 Val Tyr Pro Asp Glu GlyHis Asn Val Ser Glu Lys Ser Lys Tyr His 755 760 765 Leu Tyr Ser Thr IleLeu Lys Phe Phe Ser Asp Cys Leu Lys Glu Glu 770 775 780 Ile Ser Val LeuPro Gln Glu Pro Glu Glu Asp Glu 785 790 795 6 2583 DNA Homo sapiens 6gcctgggatt gtgcactgtc cagggtcctg aaacatgaac caaactgcca gcgtgtccca 60tcacatcaag tgtcaaccct caaaaacaat caaggaactg ggaagtaaca gccctccaca 120gagaaactgg aagggaattg ctattgctct gctggtgatt ttagttgtat gctcactcat 180cactatgtca gtcatcctct taagcccaga tgaactcaca aattcgtcag aaaccagatt 240gtctttggaa gacctcttta ggaaagactt tgtgcttcac gatccagagg ctcggtggat 300caatgataca gatgtggtgt ataaaagcga gaatggacat gtcattaaac tgaatataga 360aacaaatgct accacattat tattggaaaa cacaactttt gtaaccttca aagcatcaag 420acattcagtt tcaccagatt taaaatatgt ccttctggca tatgatgtca aacagatttt 480tcattattcg tatactgctt catatgtgat ttacaacata cacactaggg aagtttggga 540gttaaatcct ccagaagtag aggactccgt cttgcagtac gcggcctggg gtgtccaagg 600gcagcagctg atttatattt ttgaaaataa tatctactat caacctgata taaagagcag 660ttcattgcga ctgacatctt ctggaaaaga agaaataatt tttaatggga ttgctgactg 720gttatatgaa gaggaactcc tgcattctca catcgcccac tggtggtcac cagatggaga 780aagacttgcc ttcctgatga taaatgactc tttggtaccc accatggtta tccctcggtt 840tactggagcg ttgtatccca aaggaaagca gtatccgtat cctaaggcag gtcaagtgaa 900cccaacaata aaattatatg ttgtaaacct gtatggacca actcacactt tggagctcat 960gccacctgac agctttaaat caagagaata ctatatcact atggttaaat gggtaagcaa 1020taccaagact gtggtaagat ggttaaaccg acctcagaac atctccatcc tcacagtctg 1080tgagaccact acaggtgctt gtagtaaaaa atatgagatg acatcagata cgtggctctc 1140tcagcagaat gaggagcccg tgttttctag agacggcagc aaattcttta tgacagtgcc 1200tgttaagcaa gggggacgtg gagaatttca ccacatagct atgttcctca tccagagtaa 1260aagtgagcaa attaccgtgc ggcatctgac atcaggaaac tgggaagtga taaagatctt 1320ggcatacgat gaaactactc aaaaaattta ctttctgagc actgaatctt ctcccagagg 1380aaggcagctg tacagtgctt ctactgaagg attattgaat cgccaatgca tttcatgtaa 1440tttcatgaaa gaacaatgta catattttga tgccagtttt agtcccatga atcaacattt 1500cttattattc tgtgaaggtc caagggtccc agtggtcagc ctacatagta cggacaaccc 1560agcaaaatat tttatattgg aaagcaattc tatgctgaag gaagctatcc tgaagaagaa 1620gataggaaag ccagaaatta aaatccttca tattgacgac tatgaacttc ctttacagtt 1680gtcccttccc aaagatttta tggaccgaaa ccagtatgct cttctgttaa taatggatga 1740agaaccagga ggccagctgg ttacagataa gttccatatt gactgggatt ccgtactcat 1800tgacatggat aatgtcattg tagcaagatt tgatggcaga ggaagtggat tccagggtct 1860gaaaattttg caggagattc atcgaagatt aggttcagta gaagtaaagg accaaataac 1920agctgtgaaa tttttgctga aactgcctta cattgactcc aaaagattaa gcatttttgg 1980aaagggttat ggtggctata ttgcatcaat gatcttaaaa tcagatgaaa agctttttaa 2040atgtggatcc gtggttgcac ctatcacaga cttgaaattg tatgcctcag ctttctctga 2100aagatacctt gggatgccat ctaaggaaga aagcacttac caggcagcca gtgtgctaca 2160taatgttcat ggcttgaaag aagaaaatat attaataatt catggaactg ctgacacaaa 2220agttcatttc caacactcag cagaattaat caagcaccta ataaaagctg gagtgaatta 2280tactatgcag gtctacccag atgaaggtca taacgtatct gagaagagca agtatcatct 2340ctacagcaca atcctcaaat tcttcagtga ttgtttgaag gaagaaatat ctgtgctacc 2400acaggaacca gaagaagatg aataatggac cgtatttata cagaactgaa gggaatattg 2460aggctcaatg aaacctgaca aagagactgt aatattgtag ttgctccaga atgtcaaggg 2520cagcttacgg agatgtcact ggagcagcac gctcagagac agtgaactag catttgaata 2580cac 2583 7 690 PRT Homo sapiens 7 Met Ala Ala Ala Met Glu Thr Glu GlnLeu Gly Val Glu Ile Phe Glu 1 5 10 15 Thr Ala Asp Cys Glu Glu Asn IleGlu Ser Gln Asp Arg Pro Lys Leu 20 25 30 Glu Pro Phe Tyr Val Glu Arg TyrSer Trp Ser Gln Leu Lys Lys Leu 35 40 45 Leu Ala Asp Thr Arg Lys Tyr HisGly Tyr Met Met Ala Lys Ala Pro 50 55 60 His Asp Phe Met Phe Val Lys ArgAsn Asp Pro Asp Gly Pro His Ser 65 70 75 80 Asp Arg Ile Tyr Tyr Leu AlaMet Ser Gly Glu Asn Arg Glu Asn Thr 85 90 95 Leu Phe Tyr Ser Glu Ile ProLys Thr Ile Asn Arg Ala Ala Val Leu 100 105 110 Met Leu Ser Trp Lys ProLeu Leu Asp Leu Phe Gln Ala Thr Leu Asp 115 120 125 Tyr Gly Met Tyr SerArg Glu Glu Glu Leu Leu Arg Glu Arg Lys Arg 130 135 140 Ile Gly Thr ValGly Ile Ala Ser Tyr Asp Tyr His Gln Gly Ser Gly 145 150 155 160 Thr PheLeu Phe Gln Ala Gly Ser Gly Ile Tyr His Val Lys Asp Gly 165 170 175 GlyPro Gln Gly Phe Thr Gln Gln Pro Leu Arg Pro Asn Leu Val Glu 180 185 190Thr Ser Cys Pro Asn Ile Arg Met Asp Pro Lys Leu Cys Pro Ala Asp 195 200205 Pro Asp Trp Ile Ala Phe Ile His Ser Asn Asp Ile Trp Ile Ser Asn 210215 220 Ile Val Thr Arg Glu Glu Arg Arg Leu Thr Tyr Val His Asn Glu Leu225 230 235 240 Ala Asn Met Glu Glu Asp Ala Arg Ser Ala Gly Val Ala ThrPhe Val 245 250 255 Leu Gln Glu Glu Phe Asp Arg Tyr Ser Gly Tyr Trp TrpCys Pro Lys 260 265 270 Ala Glu Thr Thr Pro Ser Gly Gly Lys Ile Leu ArgIle Leu Tyr Glu 275 280 285 Glu Asn Asp Glu Ser Glu Val Glu Ile Ile HisVal Thr Ser Pro Met 290 295 300 Leu Glu Thr Arg Arg Ala Asp Ser Phe ArgTyr Pro Lys Thr Gly Thr 305 310 315 320 Ala Asn Pro Lys Val Thr Phe LysMet Ser Glu Ile Met Ile Asp Ala 325 330 335 Glu Gly Arg Ile Ile Asp ValIle Asp Lys Glu Leu Ile Gln Pro Phe 340 345 350 Glu Ile Leu Phe Glu GlyVal Glu Tyr Ile Ala Arg Ala Gly Trp Thr 355 360 365 Pro Glu Gly Lys TyrAla Trp Ser Ile Leu Leu Asp Arg Ser Gln Thr 370 375 380 Arg Leu Gln IleVal Leu Ile Ser Pro Glu Leu Phe Ile Pro Val Glu 385 390 395 400 Asp AspVal Met Glu Arg Gln Arg Leu Ile Glu Ser Val Pro Asp Ser 405 410 415 ValThr Pro Leu Ile Ile Tyr Glu Glu Thr Thr Asp Ile Trp Ile Asn 420 425 430Ile His Asp Ile Phe His Val Phe Pro Gln Ser His Glu Glu Glu Ile 435 440445 Glu Phe Ile Phe Ala Ser Glu Cys Lys Thr Gly Phe Arg His Leu Tyr 450455 460 Lys Ile Thr Ser Ile Leu Lys Glu Ser Lys Tyr Lys Arg Ser Ser Gly465 470 475 480 Gly Leu Pro Ala Pro Ser Asp Phe Lys Cys Pro Ile Lys GluGlu Ile 485 490 495 Ala Ile Thr Ser Gly Glu Trp Glu Val Leu Gly Arg HisGly Ser Asn 500 505 510 Ile Gln Val Asp Glu Val Arg Arg Leu Val Tyr PheGlu Gly Thr Lys 515 520 525 Asp Ser Pro Leu Glu His His Leu Tyr Val ValSer Tyr Val Asn Pro 530 535 540 Gly Glu Val Thr Arg Leu Thr Asp Arg GlyTyr Ser His Ser Cys Cys 545 550 555 560 Ile Ser Gln His Cys Asp Phe PheIle Ser Lys Tyr Ser Asn Gln Lys 565 570 575 Asn Pro His Cys Val Ser LeuTyr Lys Leu Ser Ser Pro Glu Asp Asp 580 585 590 Pro Thr Cys Lys Thr LysGlu Phe Trp Ala Thr Ile Leu Asp Ser Ala 595 600 605 Gly Pro Leu Pro AspTyr Thr Pro Pro Glu Ile Phe Ser Phe Glu Ser 610 615 620 Thr Thr Gly PheThr Leu Tyr Gly Met Leu Tyr Lys Pro His Asp Leu 625 630 635 640 Gln ProGly Lys Lys Tyr Pro Thr Val Leu Phe Ile Tyr Gly Gly Arg 645 650 655 LeuLeu Leu Leu Gly Pro Gln Ser Leu Cys Gly Ser Ser Met Ile Gln 660 665 670Asp Thr Arg Asn Val Ile Trp Val Thr Leu Thr Arg Met Asn Arg Ala 675 680685 Ile Thr 690 8 4523 DNA Homo sapiens 8 aagtgctaaa gcctccgaggccaaggccgc tgctactgcc gccgctgctt cttagtgccg 60 cgttcgccgc ctgggttgtcaccggcgccg ccgccgagga agccactgca accaggaccg 120 gagtggaggc ggcgcagcatgaagcggcgc aggcccgctc catagcgcac gtcgggacgg 180 tccgggcggg gccggggggaaggaaaatgc aacatggcag cagcaatgga aacagaacag 240 ctgggtgttg agatatttgaaactgcggac tgtgaggaga atattgaatc acaggatcgg 300 cctaaattgg agcctttttatgttgagcgg tattcctgga gtcagcttaa aaagctgctt 360 gccgatacca gaaaatatcatggctacatg atggctaagg caccacatga tttcatgttt 420 gtgaagagga atgatccagatggacctcat tcagacagaa tctattacct tgccatgtct 480 ggtgagaaca gagaaaatacactgttttat tctgaaattc ccaaaactat caatagagca 540 gcagtcttaa tgctctcttggaagcctctt ttggatcttt ttcaggcaac actggactat 600 ggaatgtatt ctcgagaagaagaactatta agagaaagaa aacgcattgg aacagtcgga 660 attgcttctt acgattatcaccaaggaagt ggaacatttc tgtttcaagc cggtagtgga 720 atttatcacg taaaagatggagggccacaa ggatttacgc aacaaccttt aaggcccaat 780 ctagtggaaa ctagttgtcccaacatacgg atggatccaa aattatgccc tgctgatcca 840 gactggattg cttttatacatagcaacgat atttggatat ctaacatcgt aaccagagaa 900 gaaaggagac tcacttatgtgcacaatgag ctagccaaca tggaagaaga tgccagatca 960 gctggagtcg ctacctttgttctccaagaa gaatttgata gatattctgg ctattggtgg 1020 tgtccaaaag ctgaaacaactcccagtggt ggtaaaattc ttagaattct atatgaagaa 1080 aatgatgaat ctgaggtggaaattattcat gttacatccc ctatgttgga aacaaggagg 1140 gcagattcat tccgttatcctaaaacaggt acagcaaatc ctaaagtcac ttttaagatg 1200 tcagaaataa tgattgatgctgaaggaagg atcatagatg tcatagataa ggaactaatt 1260 caaccttttg agattctatttgaaggagtt gaatatattg ccagagctgg atggactcct 1320 gagggaaaat atgcttggtccatcctacta gatcgctccc agactcgcct acagatagtg 1380 ttgatctcac ctgaattatttatcccagta gaagatgatg ttatggaaag gcagagactc 1440 attgagtcag tgcctgattctgtgacgcca ctaattatct atgaagaaac aacagacatc 1500 tggataaata tccatgacatctttcatgtt tttccccaaa gtcacgaaga ggaaattgag 1560 tttatttttg cctctgaatgcaaaacaggt ttccgtcatt tatacaaaat tacatctatt 1620 ttaaaggaaa gcaaatataaacgatccagt ggtgggctgc ctgctccaag tgatttcaag 1680 tgtcctatca aagaggagatagcaattacc agtggtgaat gggaagttct tggccggcat 1740 ggatctaata tccaagttgatgaagtcaga aggctggtat attttgaagg caccaaagac 1800 tcccctttag agcatcacctgtacgtagtc agttacgtaa atcctggaga ggtgacaagg 1860 ctgactgacc gtggctactcacattcttgc tgcatcagtc agcactgtga cttctttata 1920 agtaagtata gtaaccagaagaatccacac tgtgtgtccc tttacaagct atcaagtcct 1980 gaagatgacc caacttgcaaaacaaaggaa ttttgggcca ccattttgga ttcagcaggt 2040 cctcttcctg actatactcctccagaaatt ttctcttttg aaagtactac tggatttaca 2100 ttgtatggga tgctctacaagcctcatgat ctacagcctg gaaagaaata tcctactgtg 2160 ctgttcatat atggtggtcggttgctattg ctggggcccc agtcactctg tggatcttct 2220 atgatacagg atacacggaacgttatatgg gtcaccctga ccagaatgaa cagggctatt 2280 acttaggatc tgtggccatgcaagcagaaa agttcccctc tgaaccaaat cgtttactgc 2340 tcttacatgg tttcctggatgagaatgtcc attttgcaca taccagtata ttactgagtt 2400 ttttagtgag ggctggaaagccatatgatt tacagatcta tcctcaggag agacacagca 2460 taagagttcc tgaatcgggagaacattatg aactgcatct tttgcactac cttcaagaaa 2520 accttggatc acgtattgctgctctaaaag tgatataatt ttgacctgtg tagaactctc 2580 tggtatacac tggctatttaaccaaatgag gaggtttaat caacagaaaa cacagaattg 2640 atcatcacat tttgatacctgccatgtaac atctactcct gaaaataaat gtggtgccat 2700 gcaggggtct acggtttgtggtagtaatct aataccttaa ccccacatgc tcaaaatcaa 2760 atgatacata ttcctgagagacccagcaat accataagaa ttactaaaaa aaaaaaaaaa 2820 aaaaagacat tagcaccatgtattcatact accctatttt cacttttaat agtattataa 2880 acttcatgaa cttaattagtgtatttttac agtatacttt tgagtttgtt aaaatatgat 2940 gatattagtg attggtttggttcagttcca gaatctttga ctagttacag atttgatagc 3000 acttaaatgt aattgaatagcttatgcttc attgcttggg catatccagc atgttatgaa 3060 ctaataacta ttaaacttgacttaaccagt cattcattaa taatttttca aggataactt 3120 agtggcctcc taaagacacttgttttggca ctgaccagtt tttagccaat ttaatctgta 3180 tctagtataa ataattctcatttttctttg atgatattaa cagagtgggc ttttcctttt 3240 gcataaaggc tagtaactgtatatgtagca tggatttaat tagtcatgat attgataatt 3300 acaggcagaa aatttttaatcaaatgatta gagcttaaat atttgcaggc aagttttttt 3360 ttttccttta agaaaaggaaaaagtacaca ttcactagaa ttcttcagaa aatttagtgg 3420 tgccagtttc catttggtatttccttatta aaatattcta gaattttaag gagattgaag 3480 ggaatcacag tggggtggggagacctgggt ttggggaatg acagagagaa gaggtggtga 3540 gggcctgatt aaaaactaagcagaagtagt tttaacaaaa atactcatga aaatgtttgg 3600 aaactgaaat ttaaacaactgtaatattaa ggaaaccaga atcaataaat cactgtcttg 3660 ccagcacagc tacagagtaacatgattcag gggaggaaaa gttccttaga gttactttta 3720 taattctttt tttttttcctcttaggttta gaaatcttac aaatttaaac tttatccttt 3780 taaaattatt tgaacataatttagatattg taagcttaaa atacaaatgt ttatagataa 3840 cctctttacc ataaactaatccctggcaag ccatggctct cttttttttt ttggtgttta 3900 aagcctgtaa acagtttttctgaatgatca tgaacttttc ttggtttagc actaggattt 3960 agctatgaag agagctcataggctttcagg tgctaattga gatctgccct gttagagtct 4020 tggggtgcta gattggtcacattgacacca gtggcaggga aggcatctat gagtttgatg 4080 ctttttatca cacacttcagtgtttagaaa gttattacca atacttttaa acaacactcc 4140 aagaaaattt gctatatttctttctcatca ctacagagag agtagatttc cccatagaga 4200 gcacagcctc cattagtaaggttggtgact attggtaaga ggtggacttc attgacacca 4260 agtgggaggt agggaaagcccagaaatggc aggatgatat ggtggttctg tcgttgggaa 4320 aggtattggg ttttgctgtttgtatttata ctgtataata gataccacgc tttttcttat 4380 tatctgtata tgtattgcttttcatgtttg atattttccc atgccaagat ttgtttatat 4440 atattttcaa tgttaaattaaattgatttg ggtaactttc ttccccaaga aagtattttc 4500 ccccttaagt ataaatctgactg 4523 9 241 PRT Homo sapiens 9 Met Ala Ala Ala Met Glu Thr Glu GlnLeu Gly Val Glu Ile Phe Glu 1 5 10 15 Thr Ala Asp Cys Glu Glu Asn IleGlu Ser Gln Asp Arg Pro Lys Leu 20 25 30 Glu Pro Phe Tyr Val Glu Arg TyrSer Trp Ser Gln Leu Lys Lys Leu 35 40 45 Leu Ala Asp Thr Arg Lys Tyr HisGly Tyr Met Met Ala Lys Ala Pro 50 55 60 His Asp Phe Met Phe Val Lys ArgAsn Asp Pro Asp Gly Pro His Ser 65 70 75 80 Asp Arg Ile Tyr Tyr Leu AlaMet Ser Gly Glu Asn Arg Glu Asn Thr 85 90 95 Leu Phe Tyr Ser Glu Ile ProLys Thr Ile Asn Arg Ala Ala Val Leu 100 105 110 Met Leu Ser Trp Lys ProLeu Leu Asp Leu Phe Gln Ala Thr Leu Asp 115 120 125 Tyr Gly Met Tyr SerArg Glu Glu Glu Leu Leu Arg Glu Arg Lys Arg 130 135 140 Ile Gly Thr ValGly Ile Ala Ser Tyr Asp Tyr His Gln Gly Ser Gly 145 150 155 160 Thr PheLeu Phe Gln Ala Gly Ser Gly Ile Tyr His Val Lys Asp Gly 165 170 175 GlyPro Gln Gly Phe Thr Gln Gln Pro Leu Arg Pro Asn Leu Val Glu 180 185 190Thr Ser Cys Pro Asn Ile Arg Met Asp Pro Lys Leu Cys Pro Ala Asp 195 200205 Pro Asp Trp Ile Ala Phe Ile His Ser Asn Asp Ile Trp Ile Ser Asn 210215 220 Ile Val Thr Arg Glu Glu Arg Arg Leu Thr Tyr Val His Asn Gly Lys225 230 235 240 Ala 10 1356 DNA Homo sapiens 10 aagtgctaaa gcctccgaggccaaggccgc tgctactgcc gccgctgctt cttagtgccg 60 cgttcgccgc ctgggttgtcaccggcgccg ccgccgagga agccactgca accaggaccg 120 gagtggaggc ggcgcagcatgaagcggcgc aggcccgctc catagcgcac gtcgggacgg 180 tccgggcggg gccggggggaaggaaaatgc aacatggcag cagcaatgga aacagaacag 240 ctgggtgttg agatatttgaaactgcggac tgtgaggaga atattgaatc acaggatcgg 300 cctaaattgg agcctttttatgttgagcgg tattcctgga gtcagcttaa aaagctgctt 360 gccgatacca gaaaatatcatggctacatg atggctaagg caccacatga tttcatgttt 420 gtgaagagga atgatccagatggacctcat tcagacagaa tctattacct tgccatgtct 480 ggtgagaaca gagaaaatacactgttttat tctgaaattc ccaaaactat caatagagca 540 gcagtcttaa tgctctcttggaagcctctt ttggatcttt ttcaggcaac actggactat 600 ggaatgtatt ctcgagaagaagaactatta agagaaagaa aacgcattgg aacagtcgga 660 attgcttctt acgattatcaccaaggaagt ggaacatttc tgtttcaagc cggtagtgga 720 atttatcacg taaaagatggagggccacaa ggatttacgc aacaaccttt aaggcccaat 780 ctagtggaaa ctagttgtcccaacatacgg atggatccaa aattatgccc tgctgatcca 840 gactggattg cttttatacatagcaacgat atttggatat ctaacatcgt aaccagagaa 900 gaaaggagac tcacttatgtgcacaatggt aaggcgtagt tcttcagatt tacttttctg 960 aacagtattt tttgaagtataatttgctgc ttgcattttg aaattagatt accacgttgg 1020 gtgatcttta tatttgaaattcaagtcttt aaaattttta aaaaatggag aaaagtacag 1080 aggataactt gtatgtaccacatgtataat attcatttta atgttttaat gttcattttc 1140 aaacagtgaa acaaaagaacctctgacatg attgttcttt tagcttgcta agactgccag 1200 aattttccca aaactgttcttattaaaata aaattttagg ctaggcatgg tggctcatgc 1260 ctgtaatcct agcactctgggaggctgagg caggcagatt gtttgagccc agaagttcaa 1320 gatcaggatg ggcaacatggtgacacctcg tttgac 1356 11 661 PRT Homo sapiens 11 Met Ala Ala Ala MetGlu Thr Glu Gln Leu Gly Val Glu Ile Phe Glu 1 5 10 15 Thr Ala Asp CysGlu Glu Asn Ile Glu Ser Gln Asp Arg Pro Lys Leu 20 25 30 Glu Pro Phe TyrVal Glu Arg Tyr Ser Trp Ser Gln Leu Lys Lys Leu 35 40 45 Leu Ala Asp ThrArg Lys Tyr His Gly Tyr Met Met Ala Lys Ala Pro 50 55 60 His Asp Phe MetPhe Val Lys Arg Asn Asp Pro Asp Gly Pro His Ser 65 70 75 80 Asp Arg IleTyr Tyr Leu Ala Met Ser Gly Glu Asn Arg Glu Asn Thr 85 90 95 Leu Phe TyrSer Glu Ile Pro Lys Thr Ile Asn Arg Ala Ala Val Leu 100 105 110 Met LeuSer Trp Lys Pro Leu Leu Asp Leu Phe Gln Ala Thr Leu Asp 115 120 125 TyrGly Met Tyr Ser Arg Glu Glu Glu Leu Leu Arg Glu Arg Lys Arg 130 135 140Ile Gly Thr Val Gly Ile Ala Ser Tyr Asp Tyr His Gln Gly Ser Gly 145 150155 160 Thr Phe Leu Phe Gln Ala Gly Ser Gly Ile Tyr His Val Lys Asp Gly165 170 175 Gly Pro Gln Gly Phe Thr Gln Gln Pro Leu Arg Pro Asn Leu ValGlu 180 185 190 Thr Ser Cys Pro Asn Ile Arg Met Asp Pro Lys Leu Cys ProAla Asp 195 200 205 Pro Asp Trp Ile Ala Phe Ile His Ser Asn Asp Ile TrpIle Ser Asn 210 215 220 Ile Val Thr Arg Glu Glu Arg Arg Leu Thr Tyr ValHis Asn Glu Leu 225 230 235 240 Ala Asn Met Glu Glu Asp Ala Arg Ser AlaGly Val Ala Thr Phe Val 245 250 255 Leu Gln Glu Glu Phe Asp Arg Tyr SerGly Tyr Trp Trp Cys Pro Lys 260 265 270 Ala Glu Thr Thr Pro Ser Gly GlyLys Ile Leu Arg Ile Leu Tyr Glu 275 280 285 Glu Asn Asp Glu Ser Glu ValGlu Ile Ile His Val Thr Ser Pro Met 290 295 300 Leu Glu Thr Arg Arg AlaAsp Ser Phe Arg Tyr Pro Lys Thr Gly Thr 305 310 315 320 Ala Asn Pro LysVal Thr Phe Lys Met Ser Glu Ile Met Ile Asp Ala 325 330 335 Glu Gly ArgIle Ile Asp Val Ile Asp Lys Glu Leu Ile Gln Pro Phe 340 345 350 Glu IleLeu Phe Glu Gly Val Glu Tyr Ile Ala Arg Ala Gly Trp Thr 355 360 365 ProGlu Gly Lys Tyr Ala Trp Ser Ile Leu Leu Asp Arg Ser Gln Thr 370 375 380Arg Leu Gln Ile Val Leu Ile Ser Pro Glu Leu Phe Ile Pro Val Glu 385 390395 400 Asp Asp Val Met Glu Arg Gln Arg Leu Ile Glu Ser Val Pro Asp Ser405 410 415 Val Thr Pro Leu Ile Ile Tyr Glu Glu Thr Thr Asp Ile Trp IleAsn 420 425 430 Ile His Asp Ile Phe His Val Phe Pro Gln Ser His Glu GluGlu Ile 435 440 445 Glu Phe Ile Phe Ala Ser Glu Cys Lys Thr Gly Phe ArgHis Leu Tyr 450 455 460 Lys Ile Thr Ser Ile Leu Lys Glu Ser Lys Tyr LysArg Ser Ser Gly 465 470 475 480 Gly Leu Pro Ala Pro Ser Asp Phe Lys CysPro Ile Lys Glu Glu Ile 485 490 495 Ala Ile Thr Ser Gly Glu Trp Glu ValLeu Gly Arg His Gly Ser Asn 500 505 510 Ile Gln Val Asp Glu Val Arg ArgLeu Val Tyr Phe Glu Gly Thr Lys 515 520 525 Asp Ser Pro Leu Glu His HisLeu Tyr Val Val Ser Tyr Val Asn Pro 530 535 540 Gly Glu Val Thr Arg LeuThr Asp Arg Gly Tyr Ser His Ser Cys Cys 545 550 555 560 Ile Ser Gln HisCys Asp Phe Phe Ile Ser Lys Tyr Ser Asn Gln Lys 565 570 575 Asn Pro HisCys Val Ser Leu Tyr Lys Leu Ser Ser Pro Glu Asp Asp 580 585 590 Pro ThrCys Lys Thr Lys Glu Phe Trp Ala Thr Ile Leu Asp Ser Ala 595 600 605 GlyPro Leu Pro Asp Tyr Thr Pro Pro Glu Ile Phe Ser Phe Glu Ser 610 615 620Thr Thr Gly Phe Thr Leu Tyr Gly Met Leu Tyr Lys Pro His Asp Leu 625 630635 640 Gln Pro Gly Lys Lys Tyr Pro Thr Val Leu Phe Ile Tyr Gly Gly Leu645 650 655 Leu Arg Cys Ser Trp 660 12 4829 DNA Homo sapiens 12aagtgctaaa gcctccgagg ccaaggccgc tgctactgcc gccgctgctt cttagtgccg 60cgttcgccgc ctgggttgtc accggcgccg ccgccgagga agccactgca accaggaccg 120gagtggaggc ggcgcagcat gaagcggcgc aggcccgctc catagcgcac gtcgggacgg 180tccgggcggg gccgggggga aggaaaatgc aacatggcag cagcaatgga aacagaacag 240ctgggtgttg agatatttga aactgcggac tgtgaggaga atattgaatc acaggatcgg 300cctaaattgg agccttttta tgttgagcgg tattcctgga gtcagcttaa aaagctgctt 360gccgatacca gaaaatatca tggctacatg atggctaagg caccacatga tttcatgttt 420gtgaagagga atgatccaga tggacctcat tcagacagaa tctattacct tgccatgtct 480ggtgagaaca gagaaaatac actgttttat tctgaaattc ccaaaactat caatagagca 540gcagtcttaa tgctctcttg gaagcctctt ttggatcttt ttcaggcaac actggactat 600ggaatgtatt ctcgagaaga agaactatta agagaaagaa aacgcattgg aacagtcgga 660attgcttctt acgattatca ccaaggaagt ggaacatttc tgtttcaagc cggtagtgga 720atttatcacg taaaagatgg agggccacaa ggatttacgc aacaaccttt aaggcccaat 780ctagtggaaa ctagttgtcc caacatacgg atggatccaa aattatgccc tgctgatcca 840gactggattg cttttataca tagcaacgat atttggatat ctaacatcgt aaccagagaa 900gaaaggagac tcacttatgt gcacaatgag ctagccaaca tggaagaaga tgccagatca 960gctggagtcg ctacctttgt tctccaagaa gaatttgata gatattctgg ctattggtgg 1020tgtccaaaag ctgaaacaac tcccagtggt ggtaaaattc ttagaattct atatgaagaa 1080aatgatgaat ctgaggtgga aattattcat gttacatccc ctatgttgga aacaaggagg 1140gcagattcat tccgttatcc taaaacaggt acagcaaatc ctaaagtcac ttttaagatg 1200tcagaaataa tgattgatgc tgaaggaagg atcatagatg tcatagataa ggaactaatt 1260caaccttttg agattctatt tgaaggagtt gaatatattg ccagagctgg atggactcct 1320gagggaaaat atgcttggtc catcctacta gatcgctccc agactcgcct acagatagtg 1380ttgatctcac ctgaattatt tatcccagta gaagatgatg ttatggaaag gcagagactc 1440attgagtcag tgcctgattc tgtgacgcca ctaattatct atgaagaaac aacagacatc 1500tggataaata tccatgacat ctttcatgtt tttccccaaa gtcacgaaga ggaaattgag 1560tttatttttg cctctgaatg caaaacaggt ttccgtcatt tatacaaaat tacatctatt 1620ttaaaggaaa gcaaatataa acgatccagt ggtgggctgc ctgctccaag tgatttcaag 1680tgtcctatca aagaggagat agcaattacc agtggtgaat gggaagttct tggccggcat 1740ggatctaata tccaagttga tgaagtcaga aggctggtat attttgaagg caccaaagac 1800tcccctttag agcatcacct gtacgtagtc agttacgtaa atcctggaga ggtgacaagg 1860ctgactgacc gtggctactc acattcttgc tgcatcagtc agcactgtga cttctttata 1920agtaagtata gtaaccagaa gaatccacac tgtgtgtccc tttacaagct atcaagtcct 1980gaagatgacc caacttgcaa aacaaaggaa ttttgggcca ccattttgga ttcagcaggt 2040cctcttcctg actatactcc tccagaaatt ttctcttttg aaagtactac tggatttaca 2100ttgtatggga tgctctacaa gcctcatgat ctacagcctg gaaagaaata tcctactgtg 2160ctgttcatat atggtggtct cctcaggtgc agttggtgaa taatcggttt aaaggagtca 2220agtatttccg cttgaatacc ctagcctctc taggttatgt ggttgtagtg atagacaaca 2280ggggatcctg tcaccgaggg cttaaatttg aaggcgcctt taaatataaa atgggtcaaa 2340tagaaattga cgatcaggtg gaaggactcc aatatctagc ttctcgatat gatttcattg 2400acttagatcg tgtgggcatc cacggctggt cctatggagg atacctctcc ctgatggcat 2460taatgcagag gtcagatatc ttcagggttg ctattgctgg ggccccagtc actctgtgga 2520tcttctatga tacaggatac acggaacgtt atatgggtca ccctgaccag aatgaacagg 2580gctattactt aggatctgtg gccatgcaag cagaaaagtt cccctctgaa ccaaatcgtt 2640tactgctctt acatggtttc ctggatgaga atgtccattt tgcacatacc agtatattac 2700tgagtttttt agtgagggct ggaaagccat atgatttaca gatctatcct caggagagac 2760acagcataag agttcctgaa tcgggagaac attatgaact gcatcttttg cactaccttc 2820aagaaaacct tggatcacgt attgctgctc taaaagtgat ataattttga cctgtgtaga 2880actctctggt atacactggc tatttaacca aatgaggagg tttaatcaac agaaaacaca 2940gaattgatca tcacattttg atacctgcca tgtaacatct actcctgaaa ataaatgtgg 3000tgccatgcag gggtctacgg tttgtggtag taatctaata ccttaacccc acatgctcaa 3060aatcaaatga tacatattcc tgagagaccc agcaatacca taagaattac taaaaaaaaa 3120aaaaaaaaaa agacattagc accatgtatt catactaccc tattttcact tttaatagta 3180ttataaactt catgaactta attagtgtat ttttacagta tacttttgag tttgttaaaa 3240tatgatgata ttagtgattg gtttggttca gttccagaat ctttgactag ttacagattt 3300gatagcactt aaatgtaatt gaatagctta tgcttcattg cttgggcata tccagcatgt 3360tatgaactaa taactattaa acttgactta accagtcatt cattaataat ttttcaagga 3420taacttagtg gcctcctaaa gacacttgtt ttggcactga ccagttttta gccaatttaa 3480tctgtatcta gtataaataa ttctcatttt tctttgatga tattaacaga gtgggctttt 3540ccttttgcat aaaggctagt aactgtatat gtagcatgga tttaattagt catgatattg 3600ataattacag gcagaaaatt tttaatcaaa tgattagagc ttaaatattt gcaggcaagt 3660tttttttttt cctttaagaa aaggaaaaag tacacattca ctagaattct tcagaaaatt 3720tagtggtgcc agtttccatt tggtatttcc ttattaaaat attctagaat tttaaggaga 3780ttgaagggaa tcacagtggg gtggggagac ctgggtttgg ggaatgacag agagaagagg 3840tggtgagggc ctgattaaaa actaagcaga agtagtttta acaaaaatac tcatgaaaat 3900gtttggaaac tgaaatttaa acaactgtaa tattaaggaa accagaatca ataaatcact 3960gtcttgccag cacagctaca gagtaacatg attcagggga ggaaaagttc cttagagtta 4020cttttataat tctttttttt tttcctctta ggtttagaaa tcttacaaat ttaaacttta 4080tccttttaaa attatttgaa cataatttag atattgtaag cttaaaatac aaatgtttat 4140agataacctc tttaccataa actaatccct ggcaagccat ggctctcttt ttttttttgg 4200tgtttaaagc ctgtaaacag tttttctgaa tgatcatgaa cttttcttgg tttagcacta 4260ggatttagct atgaagagag ctcataggct ttcaggtgct aattgagatc tgccctgtta 4320gagtcttggg gtgctagatt ggtcacattg acaccagtgg cagggaaggc atctatgagt 4380ttgatgcttt ttatcacaca cttcagtgtt tagaaagtta ttaccaatac ttttaaacaa 4440cactccaaga aaatttgcta tatttctttc tcatcactac agagagagta gatttcccca 4500tagagagcac agcctccatt agtaaggttg gtgactattg gtaagaggtg gacttcattg 4560acaccaagtg ggaggtaggg aaagcccaga aatggcagga tgatatggtg gttctgtcgt 4620tgggaaaggt attgggtttt gctgtttgta tttatactgt ataatagata ccacgctttt 4680tcttattatc tgtatatgta ttgcttttca tgtttgatat tttcccatgc caagatttgt 4740ttatatatat tttcaatgtt aaattaaatt gatttgggta actttcttcc ccaagaaagt 4800attttccccc ttaagtataa atctgactg 4829 13 358 PRT Homo sapiens 13 Met AlaAla Ala Met Glu Thr Glu Gln Leu Gly Val Glu Ile Phe Glu 1 5 10 15 ThrAla Asp Cys Glu Glu Asn Ile Glu Ser Gln Asp Arg Pro Lys Leu 20 25 30 GluPro Phe Tyr Val Glu Arg Tyr Ser Trp Ser Gln Leu Lys Lys Leu 35 40 45 LeuAla Asp Thr Arg Lys Tyr His Gly Tyr Met Met Ala Lys Ala Pro 50 55 60 HisAsp Phe Met Phe Val Lys Arg Asn Asp Pro Asp Gly Pro His Ser 65 70 75 80Asp Arg Ile Tyr Tyr Leu Ala Met Ser Gly Glu Asn Arg Glu Asn Thr 85 90 95Leu Phe Tyr Ser Glu Ile Pro Lys Thr Ile Asn Arg Ala Ala Val Leu 100 105110 Met Leu Ser Trp Lys Pro Leu Leu Asp Leu Phe Gln Ala Thr Leu Asp 115120 125 Tyr Gly Met Tyr Ser Arg Glu Glu Glu Leu Leu Arg Glu Arg Lys Arg130 135 140 Ile Gly Thr Val Gly Ile Ala Ser Tyr Asp Tyr His Gln Gly SerGly 145 150 155 160 Thr Phe Leu Phe Gln Ala Gly Ser Gly Ile Tyr His ValLys Asp Gly 165 170 175 Gly Pro Gln Gly Phe Thr Gln Gln Pro Leu Arg ProAsn Leu Val Glu 180 185 190 Thr Ser Cys Pro Asn Ile Arg Met Asp Pro LysLeu Cys Pro Ala Asp 195 200 205 Pro Asp Trp Ile Ala Phe Ile His Ser AsnAsp Ile Trp Ile Ser Asn 210 215 220 Ile Val Thr Arg Glu Glu Arg Arg LeuThr Tyr Val His Asn Glu Leu 225 230 235 240 Ala Asn Met Glu Glu Asp AlaArg Ser Ala Gly Val Ala Thr Phe Val 245 250 255 Leu Gln Glu Glu Phe AspArg Tyr Ser Gly Tyr Trp Trp Cys Pro Lys 260 265 270 Ala Glu Thr Thr ProSer Gly Gly Lys Ile Leu Arg Ile Leu Tyr Glu 275 280 285 Glu Asn Asp GluSer Glu Val Glu Ile Ile His Val Thr Ser Pro Met 290 295 300 Leu Glu ThrArg Arg Ala Asp Ser Phe Arg Tyr Pro Lys Thr Gly Thr 305 310 315 320 AlaAsn Pro Lys Val Thr Phe Lys Met Ser Glu Ile Met Ile Asp Ala 325 330 335Glu Gly Arg Ser Lys Leu Met Lys Ser Glu Gly Trp Tyr Ile Leu Lys 340 345350 Ala Pro Lys Thr Pro Leu 355 14 4309 DNA Homo sapiens 14 aagtgctaaagcctccgagg ccaaggccgc tgctactgcc gccgctgctt cttagtgccg 60 cgttcgccgcctgggttgtc accggcgccg ccgccgagga agccactgca accaggaccg 120 gagtggaggcggcgcagcat gaagcggcgc aggcccgctc catagcgcac gtcgggacgg 180 tccgggcggggccgggggga aggaaaatgc aacatggcag cagcaatgga aacagaacag 240 ctgggtgttgagatatttga aactgcggac tgtgaggaga atattgaatc acaggatcgg 300 cctaaattggagccttttta tgttgagcgg tattcctgga gtcagcttaa aaagctgctt 360 gccgataccagaaaatatca tggctacatg atggctaagg caccacatga tttcatgttt 420 gtgaagaggaatgatccaga tggacctcat tcagacagaa tctattacct tgccatgtct 480 ggtgagaacagagaaaatac actgttttat tctgaaattc ccaaaactat caatagagca 540 gcagtcttaatgctctcttg gaagcctctt ttggatcttt ttcaggcaac actggactat 600 ggaatgtattctcgagaaga agaactatta agagaaagaa aacgcattgg aacagtcgga 660 attgcttcttacgattatca ccaaggaagt ggaacatttc tgtttcaagc cggtagtgga 720 atttatcacgtaaaagatgg agggccacaa ggatttacgc aacaaccttt aaggcccaat 780 ctagtggaaactagttgtcc caacatacgg atggatccaa aattatgccc tgctgatcca 840 gactggattgcttttataca tagcaacgat atttggatat ctaacatcgt aaccagagaa 900 gaaaggagactcacttatgt gcacaatgag ctagccaaca tggaagaaga tgccagatca 960 gctggagtcgctacctttgt tctccaagaa gaatttgata gatattctgg ctattggtgg 1020 tgtccaaaagctgaaacaac tcccagtggt ggtaaaattc ttagaattct atatgaagaa 1080 aatgatgaatctgaggtgga aattattcat gttacatccc ctatgttgga aacaaggagg 1140 gcagattcattccgttatcc taaaacaggt acagcaaatc ctaaagtcac ttttaagatg 1200 tcagaaataatgattgatgc tgaaggaaga tccaagttga tgaagtcaga aggctggtat 1260 attttgaaggcaccaaagac tcccctttag agcatcacct gtacgtagtc agttacgtaa 1320 atcctggagaggtgacaagg ctgactgacc gtggctactc acattcttgc tgcatcagtc 1380 agcactgtgacttctttata agtaagtata gtaaccagaa gaatccacac tgtgtgtccc 1440 tttacaagctatcaagtcct gaagatgacc caacttgcaa aacaaaggaa ttttgggcca 1500 ccattttggattcagcaggt cctcttcctg actatactcc tccagaaatt ttctcttttg 1560 aaagtactactggatttaca ttgtatggga tgctctacaa gcctcatgat ctacagcctg 1620 gaaagaaatatcctactgtg ctgttcatat atggtggtct cctcaggtgc agttggtgaa 1680 taatcggtttaaaggagtca agtatttccg cttgaatacc ctagcctctc taggttatgt 1740 ggttgtagtgatagacaaca ggggatcctg tcaccgaggg cttaaatttg aaggcgcctt 1800 taaatataaaatgggtcaaa tagaaattga cgatcaggtg gaaggactcc aatatctagc 1860 ttctcgatatgatttcattg acttagatcg tgtgggcatc cacggctggt cctatggagg 1920 atacctctccctgatggcat taatgcagag gtcagatatc ttcagggttg ctattgctgg 1980 ggccccagtcactctgtgga tcttctatga tacaggatac acggaacgtt atatgggtca 2040 ccctgaccagaatgaacagg gctattactt aggatctgtg gccatgcaag cagaaaagtt 2100 cccctctgaaccaaatcgtt tactgctctt acatggtttc ctggatgaga atgtccattt 2160 tgcacataccagtatattac tgagtttttt agtgagggct ggaaagccat atgatttaca 2220 gatctatcctcaggagagac acagcataag agttcctgaa tcgggagaac attatgaact 2280 gcatcttttgcactaccttc aagaaaacct tggatcacgt attgctgctc taaaagtgat 2340 ataattttgacctgtgtaga actctctggt atacactggc tatttaacca aatgaggagg 2400 tttaatcaacagaaaacaca gaattgatca tcacattttg atacctgcca tgtaacatct 2460 actcctgaaaataaatgtgg tgccatgcag gggtctacgg tttgtggtag taatctaata 2520 ccttaaccccacatgctcaa aatcaaatga tacatattcc tgagagaccc agcaatacca 2580 taagaattactaaaaaaaaa aaaaaaaaaa agacattagc accatgtatt catactaccc 2640 tattttcacttttaatagta ttataaactt catgaactta attagtgtat ttttacagta 2700 tacttttgagtttgttaaaa tatgatgata ttagtgattg gtttggttca gttccagaat 2760 ctttgactagttacagattt gatagcactt aaatgtaatt gaatagctta tgcttcattg 2820 cttgggcatatccagcatgt tatgaactaa taactattaa acttgactta accagtcatt 2880 cattaataatttttcaagga taacttagtg gcctcctaaa gacacttgtt ttggcactga 2940 ccagtttttagccaatttaa tctgtatcta gtataaataa ttctcatttt tctttgatga 3000 tattaacagagtgggctttt ccttttgcat aaaggctagt aactgtatat gtagcatgga 3060 tttaattagtcatgatattg ataattacag gcagaaaatt tttaatcaaa tgattagagc 3120 ttaaatatttgcaggcaagt tttttttttt cctttaagaa aaggaaaaag tacacattca 3180 ctagaattcttcagaaaatt tagtggtgcc agtttccatt tggtatttcc ttattaaaat 3240 attctagaattttaaggaga ttgaagggaa tcacagtggg gtggggagac ctgggtttgg 3300 ggaatgacagagagaagagg tggtgagggc ctgattaaaa actaagcaga agtagtttta 3360 acaaaaatactcatgaaaat gtttggaaac tgaaatttaa acaactgtaa tattaaggaa 3420 accagaatcaataaatcact gtcttgccag cacagctaca gagtaacatg attcagggga 3480 ggaaaagttccttagagtta cttttataat tctttttttt tttcctctta ggtttagaaa 3540 tcttacaaatttaaacttta tccttttaaa attatttgaa cataatttag atattgtaag 3600 cttaaaatacaaatgtttat agataacctc tttaccataa actaatccct ggcaagccat 3660 ggctctctttttttttttgg tgtttaaagc ctgtaaacag tttttctgaa tgatcatgaa 3720 cttttcttggtttagcacta ggatttagct atgaagagag ctcataggct ttcaggtgct 3780 aattgagatctgccctgtta gagtcttggg gtgctagatt ggtcacattg acaccagtgg 3840 cagggaaggcatctatgagt ttgatgcttt ttatcacaca cttcagtgtt tagaaagtta 3900 ttaccaatacttttaaacaa cactccaaga aaatttgcta tatttctttc tcatcactac 3960 agagagagtagatttcccca tagagagcac agcctccatt agtaaggttg gtgactattg 4020 gtaagaggtggacttcattg acaccaagtg ggaggtaggg aaagcccaga aatggcagga 4080 tgatatggtggttctgtcgt tgggaaaggt attgggtttt gctgtttgta tttatactgt 4140 ataatagataccacgctttt tcttattatc tgtatatgta ttgcttttca tgtttgatat 4200 tttcccatgccaagatttgt ttatatatat tttcaatgtt aaattaaatt gatttgggta 4260 actttcttccccaagaaagt attttccccc ttaagtataa atctgactg 4309 15 108 PRT Homo sapiens15 Met Ala Ala Ala Met Glu Thr Glu Gln Leu Gly Val Glu Ile Phe Glu 1 510 15 Thr Ala Asp Cys Glu Glu Asn Ile Glu Ser Gln Asp Arg Pro Lys Leu 2025 30 Glu Pro Phe Tyr Val Glu Arg Tyr Ser Trp Ser Gln Leu Lys Lys Leu 3540 45 Leu Ala Asp Thr Arg Lys Tyr His Gly Tyr Met Met Ala Lys Ala Pro 5055 60 His Asp Phe Met Phe Val Lys Arg Asn Asp Pro Asp Gly Pro His Ser 6570 75 80 Asp Arg Ile Tyr Tyr Leu Gly Asn Lys Ser Leu Ile Asp His Asp Arg85 90 95 Phe Ser Lys Ser Lys Met Pro Glu Ile Ala Ser Ser 100 105 16 620DNA Homo sapiens 16 17 194 PRT Homo sapiens 17 Met Ala Ala Ala Met GluThr Glu Gln Leu Gly Val Glu Ile Phe Glu 1 5 10 15 Thr Ala Asp Cys GluGlu Asn Ile Glu Ser Gln Asp Arg Pro Lys Leu 20 25 30 Glu Pro Phe Tyr ValGlu Arg Tyr Ser Trp Ser Gln Leu Lys Lys Leu 35 40 45 Leu Ala Asp Thr ArgLys Tyr His Gly Tyr Met Met Ala Lys Ala Pro 50 55 60 His Asp Phe Met PheVal Lys Arg Asn Asp Pro Asp Gly Pro His Ser 65 70 75 80 Asp Arg Ile TyrTyr Leu Ala Met Ser Gly Glu Asn Arg Glu Asn Thr 85 90 95 Leu Phe Tyr SerGlu Ile Pro Lys Thr Ile Asn Arg Ala Ala Val Leu 100 105 110 Met Leu SerTrp Lys Pro Leu Leu Asp Leu Phe Gln Ala Thr Leu Asp 115 120 125 Tyr GlyMet Tyr Ser Arg Glu Glu Glu Leu Leu Arg Glu Arg Lys Arg 130 135 140 IleGly Thr Val Gly Ile Ala Ser Tyr Asp Tyr His Gln Gly Ser Gly 145 150 155160 Thr Phe Leu Phe Gln Ala Gly Ser Gly Ile Tyr His Val Lys Asp Gly 165170 175 Gly Pro Gln Gly Phe Thr Gln Pro Leu Arg Pro Asn Leu Val Glu Thr180 185 190 Cys Ala 18 832 DNA Homo sapiens 18 aagtgctaaa gcctccgaggccaaggccgc tgctactgcc gccgctgctt cttagtgccg 60 cgttcgccgc ctgggttgtcaccggcgccg ccgccgagga agccactgca accaggaccg 120 gagtggaggc ggcgcagcatgaagcggcgc aggcccgctc catagcgcac gtcgggacgg 180 tccgggcggg gccggggggaaggaaaatgc aacatggcag cagcaatgga aacagaacag 240 ctgggtgttg agatatttgaaactgcggac tgtgaggaga atattgaatc acaggatcgg 300 cctaaattgg agcctttttatgttgagcgg tattcctgga gtcagcttaa aaagctgctt 360 gccgatacca gaaaatatcatggctacatg atggctaagg caccacatga tttcatgttt 420 gtgaagagga atgatccagatggacctcat tcagacagaa tctattacct tgccatgtct 480 ggtgagaaca gagaaaatacactgttttat tctgaaattc ccaaaactat caatagagca 540 gcagtcttaa tgctctcttggaagcctctt ttggatcttt ttcaggcaac actggactat 600 ggaatgtatt ctcgagaagaagaactatta agagaaagaa aacgcattgg aacagtcgga 660 attgcttctt acgattatcaccaaggaagt ggaacatttc tgtttcaagc cggtagtgga 720 atttatcacg taaaagatggagggccacaa ggatttacgc wacaaccttt aaggcccaat 780 ctagtggaaa ctasttgtsccaracytgca tgacccaatc agatcctgta ga 832 19 658 PRT Homo sapiens 19 MetAla Ala Ala Met Glu Thr Glu Gln Leu Gly Val Glu Ile Phe Glu 1 5 10 15Thr Ala Asp Cys Glu Glu Asn Ile Glu Ser Gln Asp Arg Pro Lys Leu 20 25 30Glu Pro Phe Tyr Val Glu Arg Tyr Ser Trp Ser Gln Leu Lys Lys Leu 35 40 45Leu Ala Asp Thr Arg Lys Tyr His Gly Tyr Met Met Ala Lys Ala Pro 50 55 60His Asp Phe Met Phe Val Lys Arg Asn Asp Pro Asp Gly Pro His Ser 65 70 7580 Asp Arg Ile Tyr Tyr Leu Ala Met Ser Gly Glu Asn Arg Glu Asn Thr 85 9095 Leu Phe Tyr Ser Glu Ile Pro Lys Thr Ile Asn Arg Ala Ala Val Leu 100105 110 Met Leu Ser Trp Lys Pro Leu Leu Asp Leu Phe Gln Ala Thr Leu Asp115 120 125 Tyr Gly Met Tyr Ser Arg Glu Glu Glu Leu Leu Arg Glu Arg LysArg 130 135 140 Ile Gly Thr Val Gly Ile Ala Ser Tyr Asp Tyr His Gln GlySer Gly 145 150 155 160 Thr Phe Leu Phe Gln Ala Gly Ser Gly Ile Tyr HisVal Lys Asp Gly 165 170 175 Gly Pro Gln Gly Phe Thr Gln Gln Pro Leu ArgPro Asn Leu Val Glu 180 185 190 Thr Ser Cys Pro Asn Ile Arg Met Asp ProLys Leu Cys Pro Ala Asp 195 200 205 Pro Asp Trp Ile Ala Phe Ile His SerAsn Asp Ile Trp Ile Ser Asn 210 215 220 Ile Val Thr Arg Glu Glu Arg ArgLeu Thr Tyr Val His Asn Glu Leu 225 230 235 240 Ala Asn Met Glu Glu AspAla Arg Ser Ala Gly Val Ala Thr Phe Val 245 250 255 Leu Gln Glu Glu PheAsp Arg Tyr Ser Gly Tyr Trp Trp Cys Pro Lys 260 265 270 Ala Glu Thr ThrPro Ser Gly Gly Lys Ile Leu Arg Ile Leu Tyr Glu 275 280 285 Glu Asn AspGlu Ser Glu Val Glu Ile Ile His Val Thr Ser Pro Met 290 295 300 Leu GluThr Arg Arg Ala Asp Ser Phe Arg Tyr Pro Lys Thr Gly Thr 305 310 315 320Ala Asn Pro Lys Val Thr Phe Lys Met Ser Glu Ile Met Ile Asp Ala 325 330335 Glu Gly Arg Ile Ile Asp Val Ile Asp Lys Glu Leu Ile Gln Pro Phe 340345 350 Glu Ile Leu Phe Glu Gly Val Glu Tyr Ile Ala Arg Ala Gly Trp Thr355 360 365 Pro Glu Gly Lys Tyr Ala Trp Ser Ile Leu Leu Asp Arg Ser GlnThr 370 375 380 Arg Leu Gln Ile Val Leu Ile Ser Pro Glu Leu Phe Ile ProVal Glu 385 390 395 400 Asp Asp Val Met Glu Arg Gln Arg Leu Ile Glu SerVal Pro Asp Ser 405 410 415 Val Thr Pro Leu Ile Ile Tyr Glu Glu Thr ThrAsp Ile Trp Ile Asn 420 425 430 Ile His Asp Ile Phe His Val Phe Pro GlnSer His Glu Glu Glu Ile 435 440 445 Glu Phe Ile Phe Ala Ser Glu Cys LysThr Gly Phe Arg His Leu Tyr 450 455 460 Lys Ile Thr Ser Ile Leu Lys GluSer Lys Tyr Lys Arg Ser Ser Gly 465 470 475 480 Gly Leu Pro Ala Pro SerAsp Phe Lys Cys Pro Ile Lys Glu Glu Ile 485 490 495 Ala Ile Thr Ser GlyGlu Trp Glu Val Leu Gly Arg His Gly Ser Asn 500 505 510 Ile Gln Val AspGlu Val Arg Arg Leu Val Tyr Phe Glu Gly Thr Lys 515 520 525 Asp Ser ProLeu Glu His His Leu Tyr Val Val Ser Tyr Val Asn Pro 530 535 540 Gly GluVal Thr Arg Leu Thr Asp Arg Gly Tyr Ser His Ser Cys Cys 545 550 555 560Ile Ser Gln His Cys Asp Phe Phe Ile Ser Lys Tyr Ser Asn Gln Lys 565 570575 Asn Pro His Cys Val Ser Leu Tyr Lys Leu Ser Ser Pro Glu Asp Asp 580585 590 Pro Thr Cys Lys Thr Lys Glu Phe Trp Ala Thr Ile Leu Asp Ser Ala595 600 605 Gly Pro Leu Pro Asp Tyr Thr Pro Pro Glu Ile Phe Ser Phe GluSer 610 615 620 Thr Thr Gly Phe Thr Leu Tyr Gly Met Leu Tyr Lys Pro HisAsp Leu 625 630 635 640 Gln Pro Gly Lys Lys Tyr Pro Thr Val Leu Phe IleTyr Gly Gly Arg 645 650 655 Val Lys 20 4676 DNA Homo sapiens 20aagtgctaaa gcctccgagg ccaaggccgc tgctactgcc gccgctgctt cttagtgccg 60cgttcgccgc ctgggttgtc accggcgccg ccgccgagga agccactgca accaggaccg 120gagtggaggc ggcgcagcat gaagcggcgc aggcccgctc catagcgcac gtcgggacgg 180tccgggcggg gccgggggga aggaaaatgc aacatggcag cagcaatgga aacagaacag 240ctgggtgttg agatatttga aactgcggac tgtgaggaga atattgaatc acaggatcgg 300cctaaattgg agccttttta tgttgagcgg tattcctgga gtcagcttaa aaagctgctt 360gccgatacca gaaaatatca tggctacatg atggctaagg caccacatga tttcatgttt 420gtgaagagga atgatccaga tggacctcat tcagacagaa tctattacct tgccatgtct 480ggtgagaaca gagaaaatac actgttttat tctgaaattc ccaaaactat caatagagca 540gcagtcttaa tgctctcttg gaagcctctt ttggatcttt ttcaggcaac actggactat 600ggaatgtatt ctcgagaaga agaactatta agagaaagaa aacgcattgg aacagtcgga 660attgcttctt acgattatca ccaaggaagt ggaacatttc tgtttcaagc cggtagtgga 720atttatcacg taaaagatgg agggccacaa ggatttacgc aacaaccttt aaggcccaat 780ctagtggaaa ctagttgtcc caacatacgg atggatccaa aattatgccc tgctgatcca 840gactggattg cttttataca tagcaacgat atttggatat ctaacatcgt aaccagagaa 900gaaaggagac tcacttatgt gcacaatgag ctagccaaca tggaagaaga tgccagatca 960gctggagtcg ctacctttgt tctccaagaa gaatttgata gatattctgg ctattggtgg 1020tgtccaaaag ctgaaacaac tcccagtggt ggtaaaattc ttagaattct atatgaagaa 1080aatgatgaat ctgaggtgga aattattcat gttacatccc ctatgttgga aacaaggagg 1140gcagattcat tccgttatcc taaaacaggt acagcaaatc ctaaagtcac ttttaagatg 1200tcagaaataa tgattgatgc tgaaggaagg atcatagatg tcatagataa ggaactaatt 1260caaccttttg agattctatt tgaaggagtt gaatatattg ccagagctgg atggactcct 1320gagggaaaat atgcttggtc catcctacta gatcgctccc agactcgcct acagatagtg 1380ttgatctcac ctgaattatt tatcccagta gaagatgatg ttatggaaag gcagagactc 1440attgagtcag tgcctgattc tgtgacgcca ctaattatct atgaagaaac aacagacatc 1500tggataaata tccatgacat ctttcatgtt tttccccaaa gtcacgaaga ggaaattgag 1560tttatttttg cctctgaatg caaaacaggt ttccgtcatt tatacaaaat tacatctatt 1620ttaaaggaaa gcaaatataa acgatccagt ggtgggctgc ctgctccaag tgatttcaag 1680tgtcctatca aagaggagat agcaattacc agtggtgaat gggaagttct tggccggcat 1740ggatctaata tccaagttga tgaagtcaga aggctggtat attttgaagg caccaaagac 1800tcccctttag agcatcacct gtacgtagtc agttacgtaa atcctggaga ggtgacaagg 1860ctgactgacc gtggctactc acattcttgc tgcatcagtc agcactgtga cttctttata 1920agtaagtata gtaaccagaa gaatccacac tgtgtgtccc tttacaagct atcaagtcct 1980gaagatgacc caacttgcaa aacaaaggaa ttttgggcca ccattttgga ttcagcaggt 2040cctcttcctg actatactcc tccagaaatt ttctcttttg aaagtactac tggatttaca 2100ttgtatggga tgctctacaa gcctcatgat ctacagcctg gaaagaaata tcctactgtg 2160ctgttcatat atggtggtcg ggtcaaatag aaattgacga tcaggtggaa ggactccaat 2220atctagcttc tcgatatgat ttcattgact tagatcgtgt gggcatccac ggctggtcct 2280atggaggata cctctccctg atggcattaa tgcagaggtc agatatcttc agggttgcta 2340ttgctggggc cccagtcact ctgtggatct tctatgatac aggatacacg gaacgttata 2400tgggtcaccc tgaccagaat gaacagggct attacttagg atctgtggcc atgcaagcag 2460aaaagttccc ctctgaacca aatcgtttac tgctcttaca tggtttcctg gatgagaatg 2520tccattttgc acataccagt atattactga gttttttagt gagggctgga aagccatatg 2580atttacagat ctatcctcag gagagacaca gcataagagt tcctgaatcg ggagaacatt 2640atgaactgca tcttttgcac taccttcaag aaaaccttgg atcacgtatt gctgctctaa 2700aagtgatata attttgacct gtgtagaact ctctggtata cactggctat ttaaccaaat 2760gaggaggttt aatcaacaga aaacacagaa ttgatcatca cattttgata cctgccatgt 2820aacatctact cctgaaaata aatgtggtgc catgcagggg tctacggttt gtggtagtaa 2880tctaatacct taaccccaca tgctcaaaat caaatgatac atattcctga gagacccagc 2940aataccataa gaattactaa aaaaaaaaaa aaaaaaaaga cattagcacc atgtattcat 3000actaccctat tttcactttt aatagtatta taaacttcat gaacttaatt agtgtatttt 3060tacagtatac ttttgagttt gttaaaatat gatgatatta gtgattggtt tggttcagtt 3120ccagaatctt tgactagtta cagatttgat agcacttaaa tgtaattgaa tagcttatgc 3180ttcattgctt gggcatatcc agcatgttat gaactaataa ctattaaact tgacttaacc 3240agtcattcat taataatttt tcaaggataa cttagtggcc tcctaaagac acttgttttg 3300gcactgacca gtttttagcc aatttaatct gtatctagta taaataattc tcatttttct 3360ttgatgatat taacagagtg ggcttttcct tttgcataaa ggctagtaac tgtatatgta 3420gcatggattt aattagtcat gatattgata attacaggca gaaaattttt aatcaaatga 3480ttagagctta aatatttgca ggcaagtttt tttttttcct ttaagaaaag gaaaaagtac 3540acattcacta gaattcttca gaaaatttag tggtgccagt ttccatttgg tatttcctta 3600ttaaaatatt ctagaatttt aaggagattg aagggaatca cagtggggtg gggagacctg 3660ggtttgggga atgacagaga gaagaggtgg tgagggcctg attaaaaact aagcagaagt 3720agttttaaca aaaatactca tgaaaatgtt tggaaactga aatttaaaca actgtaatat 3780taaggaaacc agaatcaata aatcactgtc ttgccagcac agctacagag taacatgatt 3840caggggagga aaagttcctt agagttactt ttataattct tttttttttt cctcttaggt 3900ttagaaatct tacaaattta aactttatcc ttttaaaatt atttgaacat aatttagata 3960ttgtaagctt aaaatacaaa tgtttataga taacctcttt accataaact aatccctggc 4020aagccatggc tctctttttt tttttggtgt ttaaagcctg taaacagttt ttctgaatga 4080tcatgaactt ttcttggttt agcactagga tttagctatg aagagagctc ataggctttc 4140aggtgctaat tgagatctgc cctgttagag tcttggggtg ctagattggt cacattgaca 4200ccagtggcag ggaaggcatc tatgagtttg atgcttttta tcacacactt cagtgtttag 4260aaagttatta ccaatacttt taaacaacac tccaagaaaa tttgctatat ttctttctca 4320tcactacaga gagagtagat ttccccatag agagcacagc ctccattagt aaggttggtg 4380actattggta agaggtggac ttcattgaca ccaagtggga ggtagggaaa gcccagaaat 4440ggcaggatga tatggtggtt ctgtcgttgg gaaaggtatt gggttttgct gtttgtattt 4500atactgtata atagatacca cgctttttct tattatctgt atatgtattg cttttcatgt 4560ttgatatttt cccatgccaa gatttgttta tatatatttt caatgttaaa ttaaattgat 4620ttgggtaact ttcttcccca agaaagtatt ttccccctta agtataaatc tgactg 4676 21613 PRT Homo sapiens 21 Met Ala Ala Ala Met Glu Thr Glu Gln Leu Gly ValGlu Ile Phe Glu 1 5 10 15 Thr Ala Asp Cys Glu Glu Asn Ile Glu Ser GlnAsp Arg Pro Lys Leu 20 25 30 Glu Pro Phe Tyr Val Glu Arg Tyr Ser Trp SerGln Leu Lys Lys Leu 35 40 45 Leu Ala Asp Thr Arg Lys Tyr His Gly Tyr MetMet Ala Lys Ala Pro 50 55 60 His Asp Phe Met Phe Val Lys Arg Asn Asp ProAsp Gly Pro His Ser 65 70 75 80 Asp Arg Ile Tyr Tyr Leu Ala Met Ser GlyGlu Asn Arg Glu Asn Thr 85 90 95 Leu Phe Tyr Ser Glu Ile Pro Lys Thr IleAsn Arg Ala Ala Val Leu 100 105 110 Met Leu Ser Trp Lys Pro Leu Leu AspLeu Phe Gln Ala Thr Leu Asp 115 120 125 Tyr Gly Met Tyr Ser Arg Glu GluGlu Leu Leu Arg Glu Arg Lys Arg 130 135 140 Ile Gly Thr Val Gly Ile AlaSer Tyr Asp Tyr His Gln Gly Ser Gly 145 150 155 160 Thr Phe Leu Phe GlnAla Gly Ser Gly Ile Tyr His Val Lys Asp Gly 165 170 175 Gly Pro Gln GlyPhe Thr Gln Gln Pro Leu Arg Pro Asn Leu Val Glu 180 185 190 Thr Ser CysPro Asn Ile Arg Met Asp Pro Lys Leu Cys Pro Ala Asp 195 200 205 Pro AspTrp Ile Ala Phe Ile His Ser Asn Asp Ile Trp Ile Ser Asn 210 215 220 IleVal Thr Arg Glu Glu Arg Arg Leu Thr Tyr Val His Asn Glu Leu 225 230 235240 Ala Asn Met Glu Glu Asp Ala Arg Ser Ala Gly Val Ala Thr Phe Val 245250 255 Leu Gln Glu Glu Phe Asp Arg Tyr Ser Gly Tyr Trp Trp Cys Pro Lys260 265 270 Ala Glu Thr Thr Pro Ser Gly Gly Lys Ile Leu Arg Ile Leu TyrGlu 275 280 285 Glu Asn Asp Glu Ser Glu Val Glu Ile Ile His Val Thr SerPro Met 290 295 300 Leu Glu Thr Arg Arg Ala Asp Ser Phe Arg Tyr Pro LysThr Gly Thr 305 310 315 320 Ala Asn Pro Lys Val Thr Phe Lys Met Ser GluIle Met Ile Asp Ala 325 330 335 Glu Gly Arg Ile Ile Asp Val Ile Asp LysGlu Leu Ile Gln Pro Phe 340 345 350 Glu Ile Leu Phe Glu Gly Val Glu TyrIle Ala Arg Ala Gly Trp Thr 355 360 365 Pro Glu Gly Lys Tyr Ala Trp SerIle Leu Leu Asp Arg Ser Gln Thr 370 375 380 Arg Leu Gln Ile Val Leu IleSer Pro Glu Leu Phe Ile Pro Val Glu 385 390 395 400 Asp Asp Val Met GluArg Gln Arg Leu Ile Glu Ser Val Pro Asp Ser 405 410 415 Val Thr Pro LeuIle Ile Tyr Glu Glu Thr Thr Asp Ile Trp Ile Asn 420 425 430 Ile His AspIle Phe His Val Phe Pro Gln Ser His Glu Glu Glu Ile 435 440 445 Glu PheIle Phe Ala Ser Glu Cys Lys Thr Gly Phe Arg His Leu Tyr 450 455 460 LysIle Thr Ser Ile Leu Lys Glu Ser Lys Tyr Lys Arg Ser Ser Gly 465 470 475480 Gly Leu Pro Ala Pro Ser Asp Phe Lys Cys Pro Ile Lys Glu Glu Ile 485490 495 Ala Ile Thr Ser Gly Glu Trp Glu Val Leu Gly Arg His Gly Ser Asn500 505 510 Ile Gln Val Asp Glu Val Arg Arg Leu Val Tyr Phe Glu Gly ThrLys 515 520 525 Asp Ser Pro Leu Glu His His Leu Tyr Val Val Ser Tyr ValAsn Pro 530 535 540 Gly Glu Val Thr Arg Leu Thr Asp Arg Gly Tyr Ser HisSer Cys Cys 545 550 555 560 Ile Ser Gln His Cys Asp Phe Phe Ile Ser LysTyr Ser Asn Gln Lys 565 570 575 Asn Pro His Cys Val Ser Leu Tyr Lys LeuSer Ser Pro Glu Asp Asp 580 585 590 Pro Thr Cys Lys Thr Lys Glu Phe TrpAla Thr Ile Leu Asp Ser Val 595 600 605 Leu Arg Cys Ser Trp 610 22 4685DNA Homo sapiens 22 aagtgctaaa gcctccgagg ccaaggccgc tgctactgccgccgctgctt cttagtgccg 60 cgttcgccgc ctgggttgtc accggcgccg ccgccgaggaagccactgca accaggaccg 120 gagtggaggc ggcgcagcat gaagcggcgc aggcccgctccatagcgcac gtcgggacgg 180 tccgggcggg gccgggggga aggaaaatgc aacatggcagcagcaatgga aacagaacag 240 ctgggtgttg agatatttga aactgcggac tgtgaggagaatattgaatc acaggatcgg 300 cctaaattgg agccttttta tgttgagcgg tattcctggagtcagcttaa aaagctgctt 360 gccgatacca gaaaatatca tggctacatg atggctaaggcaccacatga tttcatgttt 420 gtgaagagga atgatccaga tggacctcat tcagacagaatctattacct tgccatgtct 480 ggtgagaaca gagaaaatac actgttttat tctgaaattcccaaaactat caatagagca 540 gcagtcttaa tgctctcttg gaagcctctt ttggatctttttcaggcaac actggactat 600 ggaatgtatt ctcgagaaga agaactatta agagaaagaaaacgcattgg aacagtcgga 660 attgcttctt acgattatca ccaaggaagt ggaacatttctgtttcaagc cggtagtgga 720 atttatcacg taaaagatgg agggccacaa ggatttacgcaacaaccttt aaggcccaat 780 ctagtggaaa ctagttgtcc caacatacgg atggatccaaaattatgccc tgctgatcca 840 gactggattg cttttataca tagcaacgat atttggatatctaacatcgt aaccagagaa 900 gaaaggagac tcacttatgt gcacaatgag ctagccaacatggaagaaga tgccagatca 960 gctggagtcg ctacctttgt tctccaagaa gaatttgatagatattctgg ctattggtgg 1020 tgtccaaaag ctgaaacaac tcccagtggt ggtaaaattcttagaattct atatgaagaa 1080 aatgatgaat ctgaggtgga aattattcat gttacatcccctatgttgga aacaaggagg 1140 gcagattcat tccgttatcc taaaacaggt acagcaaatcctaaagtcac ttttaagatg 1200 tcagaaataa tgattgatgc tgaaggaagg atcatagatgtcatagataa ggaactaatt 1260 caaccttttg agattctatt tgaaggagtt gaatatattgccagagctgg atggactcct 1320 gagggaaaat atgcttggtc catcctacta gatcgctcccagactcgcct acagatagtg 1380 ttgatctcac ctgaattatt tatcccagta gaagatgatgttatggaaag gcagagactc 1440 attgagtcag tgcctgattc tgtgacgcca ctaattatctatgaagaaac aacagacatc 1500 tggataaata tccatgacat ctttcatgtt tttccccaaagtcacgaaga ggaaattgag 1560 tttatttttg cctctgaatg caaaacaggt ttccgtcatttatacaaaat tacatctatt 1620 ttaaaggaaa gcaaatataa acgatccagt ggtgggctgcctgctccaag tgatttcaag 1680 tgtcctatca aagaggagat agcaattacc agtggtgaatgggaagttct tggccggcat 1740 ggatctaata tccaagttga tgaagtcaga aggctggtatattttgaagg caccaaagac 1800 tcccctttag agcatcacct gtacgtagtc agttacgtaaatcctggaga ggtgacaagg 1860 ctgactgacc gtggctactc acattcttgc tgcatcagtcagcactgtga cttctttata 1920 agtaagtata gtaaccagaa gaatccacac tgtgtgtccctttacaagct atcaagtcct 1980 gaagatgacc caacttgcaa aacaaaggaa ttttgggccaccattttgga ttcagtcctc 2040 aggtgcagtt ggtgaataat cggtttaaag gagtcaagtatttccgcttg aataccctag 2100 cctctctagg ttatgtggtt gtagtgatag acaacaggggatcctgtcac cgagggctta 2160 aatttgaagg cgcctttaaa tataaaatgg gtcaaatagaaattgacgat caggtggaag 2220 gactccaata tctagcttct cgatatgatt tcattgacttagatcgtgtg ggcatccacg 2280 gctggtccta tggaggatac ctctccctga tggcattaatgcagaggtca gatatcttca 2340 gggttgctat tgctggggcc ccagtcactc tgtggatcttctatgataca ggatacacgg 2400 aacgttatat gggtcaccct gaccagaatg aacagggctattacttagga tctgtggcca 2460 tgcaagcaga aaagttcccc tctgaaccaa atcgtttactgctcttacat ggtttcctgg 2520 atgagaatgt ccattttgca cataccagta tattactgagttttttagtg agggctggaa 2580 agccatatga tttacagatc tatcctcagg agagacacagcataagagtt cctgaatcgg 2640 gagaacatta tgaactgcat cttttgcact accttcaagaaaaccttgga tcacgtattg 2700 ctgctctaaa agtgatataa ttttgacctg tgtagaactctctggtatac actggctatt 2760 taaccaaatg aggaggttta atcaacagaa aacacagaattgatcatcac attttgatac 2820 ctgccatgta acatctactc ctgaaaataa atgtggtgccatgcaggggt ctacggtttg 2880 tggtagtaat ctaatacctt aaccccacat gctcaaaatcaaatgataca tattcctgag 2940 agacccagca ataccataag aattactaaa aaaaaaaaaaaaaaaaagac attagcacca 3000 tgtattcata ctaccctatt ttcactttta atagtattataaacttcatg aacttaatta 3060 gtgtattttt acagtatact tttgagtttg ttaaaatatgatgatattag tgattggttt 3120 ggttcagttc cagaatcttt gactagttac agatttgatagcacttaaat gtaattgaat 3180 agcttatgct tcattgcttg ggcatatcca gcatgttatgaactaataac tattaaactt 3240 gacttaacca gtcattcatt aataattttt caaggataacttagtggcct cctaaagaca 3300 cttgttttgg cactgaccag tttttagcca atttaatctgtatctagtat aaataattct 3360 catttttctt tgatgatatt aacagagtgg gcttttccttttgcataaag gctagtaact 3420 gtatatgtag catggattta attagtcatg atattgataattacaggcag aaaattttta 3480 atcaaatgat tagagcttaa atatttgcag gcaagtttttttttttcctt taagaaaagg 3540 aaaaagtaca cattcactag aattcttcag aaaatttagtggtgccagtt tccatttggt 3600 atttccttat taaaatattc tagaatttta aggagattgaagggaatcac agtggggtgg 3660 ggagacctgg gtttggggaa tgacagagag aagaggtggtgagggcctga ttaaaaacta 3720 agcagaagta gttttaacaa aaatactcat gaaaatgtttggaaactgaa atttaaacaa 3780 ctgtaatatt aaggaaacca gaatcaataa atcactgtcttgccagcaca gctacagagt 3840 aacatgattc aggggaggaa aagttcctta gagttacttttataattctt tttttttttc 3900 ctcttaggtt tagaaatctt acaaatttaa actttatccttttaaaatta tttgaacata 3960 atttagatat tgtaagctta aaatacaaat gtttatagataacctcttta ccataaacta 4020 atccctggca agccatggct ctcttttttt ttttggtgtttaaagcctgt aaacagtttt 4080 tctgaatgat catgaacttt tcttggttta gcactaggatttagctatga agagagctca 4140 taggctttca ggtgctaatt gagatctgcc ctgttagagtcttggggtgc tagattggtc 4200 acattgacac cagtggcagg gaaggcatct atgagtttgatgctttttat cacacacttc 4260 agtgtttaga aagttattac caatactttt aaacaacactccaagaaaat ttgctatatt 4320 tctttctcat cactacagag agagtagatt tccccatagagagcacagcc tccattagta 4380 aggttggtga ctattggtaa gaggtggact tcattgacaccaagtgggag gtagggaaag 4440 cccagaaatg gcaggatgat atggtggttc tgtcgttgggaaaggtattg ggttttgctg 4500 tttgtattta tactgtataa tagataccac gctttttcttattatctgta tatgtattgc 4560 ttttcatgtt tgatattttc ccatgccaag atttgtttatatatattttc aatgttaaat 4620 taaattgatt tgggtaactt tcttccccaa gaaagtattttcccccttaa gtataaatct 4680 gactg 4685 23 892 PRT Homo sapiens 23 Met ArgLys Val Lys Lys Leu Arg Leu Asp Lys Glu Asn Thr Gly Ser 1 5 10 15 TrpArg Ser Phe Ser Leu Asn Ser Glu Gly Ala Glu Arg Met Ala Thr 20 25 30 ThrGly Thr Pro Thr Ala Asp Arg Gly Asp Ala Ala Ala Thr Asp Asp 35 40 45 ProAla Ala Arg Phe Gln Val Gln Lys His Ser Trp Asp Gly Leu Arg 50 55 60 SerIle Ile His Gly Ser Arg Lys Tyr Ser Gly Leu Ile Val Asn Lys 65 70 75 80Ala Pro His Asp Phe Gln Phe Val Gln Lys Thr Asp Glu Ser Gly Pro 85 90 95His Ser His Arg Leu Tyr Tyr Leu Gly Met Pro Tyr Gly Ser Arg Glu 100 105110 Asn Ser Leu Leu Tyr Ser Glu Ile Pro Lys Lys Val Arg Lys Glu Ala 115120 125 Leu Leu Leu Leu Ser Trp Lys Gln Met Leu Asp His Phe Gln Ala Thr130 135 140 Pro His His Gly Val Tyr Ser Arg Glu Glu Glu Leu Leu Arg GluArg 145 150 155 160 Lys Arg Leu Gly Val Phe Gly Ile Thr Ser Tyr Asp PheHis Ser Glu 165 170 175 Ser Gly Leu Phe Leu Phe Gln Ala Ser Asn Ser LeuPhe His Cys Arg 180 185 190 Asp Gly Gly Lys Asn Gly Phe Met Val Ser ProMet Lys Pro Leu Glu 195 200 205 Ile Lys Thr Gln Cys Ser Gly Pro Arg MetAsp Pro Lys Ile Cys Pro 210 215 220 Ala Asp Pro Ala Phe Phe Ser Phe IleAsn Asn Ser Asp Leu Trp Val 225 230 235 240 Ala Asn Ile Glu Thr Gly GluGlu Arg Arg Leu Thr Phe Cys His Gln 245 250 255 Gly Leu Ser Asn Val LeuAsp Asp Pro Lys Ser Ala Gly Val Ala Thr 260 265 270 Phe Val Ile Gln GluGlu Phe Asp Arg Phe Thr Gly Tyr Trp Trp Cys 275 280 285 Pro Thr Ala SerTrp Glu Gly Ser Glu Gly Leu Lys Thr Leu Arg Ile 290 295 300 Leu Tyr GluGlu Val Asp Glu Ser Glu Val Glu Val Ile His Val Pro 305 310 315 320 SerPro Ala Leu Glu Glu Arg Lys Thr Asp Ser Tyr Arg Tyr Pro Arg 325 330 335Thr Gly Ser Lys Asn Pro Lys Ile Ala Leu Lys Leu Ala Glu Phe Gln 340 345350 Thr Asp Ser Gln Gly Lys Ile Val Ser Thr Gln Glu Lys Glu Leu Val 355360 365 Gln Pro Phe Ser Ser Leu Phe Pro Lys Val Glu Tyr Ile Ala Arg Ala370 375 380 Gly Trp Thr Arg Asp Gly Lys Tyr Ala Trp Ala Met Phe Leu AspArg 385 390 395 400 Pro Gln Gln Trp Leu Gln Leu Val Leu Leu Pro Pro AlaLeu Phe Ile 405 410 415 Pro Ser Thr Glu Asn Glu Glu Gln Arg Leu Ala SerAla Arg Ala Val 420 425 430 Pro Arg Asn Val Gln Pro Tyr Val Val Tyr GluGlu Val Thr Asn Val 435 440 445 Trp Ile Asn Val His Asp Ile Phe Tyr ProPhe Pro Gln Ser Glu Gly 450 455 460 Glu Asp Glu Leu Cys Phe Leu Arg AlaAsn Glu Cys Lys Thr Gly Phe 465 470 475 480 Cys His Leu Tyr Lys Val ThrAla Val Leu Lys Ser Gln Gly Tyr Asp 485 490 495 Trp Ser Glu Pro Phe SerPro Gly Glu Asp Glu Phe Lys Cys Pro Ile 500 505 510 Lys Glu Glu Ile AlaLeu Thr Ser Gly Glu Trp Glu Val Leu Ala Arg 515 520 525 His Gly Ser LysIle Trp Val Asn Glu Glu Thr Lys Leu Val Tyr Phe 530 535 540 Gln Gly ThrLys Asp Thr Pro Leu Glu His His Leu Tyr Val Val Ser 545 550 555 560 TyrGlu Ala Ala Gly Glu Ile Val Arg Leu Thr Thr Pro Gly Phe Ser 565 570 575His Ser Cys Ser Met Ser Gln Asn Phe Asp Met Phe Val Ser His Tyr 580 585590 Ser Ser Val Ser Thr Pro Pro Cys Val His Val Tyr Lys Leu Ser Gly 595600 605 Pro Asp Asp Asp Pro Leu His Lys Gln Pro Arg Phe Trp Ala Ser Met610 615 620 Met Glu Ala Ala Ser Cys Pro Pro Asp Tyr Val Pro Pro Glu IlePhe 625 630 635 640 His Phe His Thr Arg Ser Asp Val Arg Leu Tyr Gly MetIle Tyr Lys 645 650 655 Pro His Ala Leu Gln Pro Gly Lys Lys His Pro ThrVal Leu Phe Val 660 665 670 Tyr Gly Gly Pro Gln Val Gln Leu Val Asn AsnSer Phe Lys Gly Ile 675 680 685 Lys Tyr Leu Arg Leu Asn Thr Leu Ala SerLeu Gly Tyr Ala Val Val 690 695 700 Val Ile Asp Gly Arg Gly Ser Cys GlnArg Gly Leu Arg Phe Glu Gly 705 710 715 720 Ala Leu Lys Asn Gln Met GlyGln Val Glu Ile Glu Asp Gln Val Glu 725 730 735 Gly Leu Gln Phe Val AlaGlu Lys Tyr Gly Phe Ile Asp Leu Ser Arg 740 745 750 Val Ala Ile His GlyTrp Ser Tyr Gly Gly Phe Leu Ser Leu Met Gly 755 760 765 Leu Ile His LysPro Gln Val Phe Lys Val Ala Ile Ala Gly Ala Pro 770 775 780 Val Thr ValTrp Met Ala Tyr Asp Thr Gly Tyr Thr Glu Arg Tyr Met 785 790 795 800 AspVal Pro Glu Asn Asn Gln His Gly Tyr Glu Ala Gly Ser Val Ala 805 810 815Leu His Val Glu Lys Leu Pro Asn Glu Pro Asn Arg Leu Leu Ile Leu 820 825830 His Gly Phe Leu Asp Glu Asn Val His Phe Phe His Thr Asn Phe Leu 835840 845 Val Ser Gln Leu Ile Arg Ala Gly Lys Pro Tyr Gln Leu Gln Ile Tyr850 855 860 Pro Asn Glu Arg His Ser Ile Arg Cys Pro Glu Ser Gly Glu HisTyr 865 870 875 880 Glu Val Thr Leu Leu His Phe Leu Gln Glu Tyr Leu 885890 24 4302 DNA Homo sapiens 24 caggccgccg cctgggtcgc tcaacttccgggtcaaaggt gcctgagccg gcgggtcccc 60 tgtgtccgcc gcggctgtcg tcccccgctcccgccacttc cggggtcgca gtcccgggca 120 tggagccgcg accgtgaggc gccgctggacccgggacgac ctgcccagtc cggccgccgc 180 cccacgtccc ggtctgtgtc ccacgcctgcagctggaatg gaggctctct ggacccttta 240 gaaggcaccc ctgccctcct gaggtcagctgagcggttaa tgcggaaggt taagaaactg 300 cgcctggaca aggagaacac cggaagttggagaagcttct cgctgaattc cgagggggct 360 gagaggatgg ccaccaccgg gaccccaacggccgaccgag gcgacgcagc cgccacagat 420 gacccggccg cccgcttcca ggtgcagaagcactcgtggg acgggctccg gagcatcatc 480 cacggcagcc gcaagtactc gggcctcattgtcaacaagg cgccccacga cttccagttt 540 gtgcagaaga cggatgagtc tgggccccactcccaccgcc tctactacct gggaatgcca 600 tatggcagcc gagagaactc cctcctctactctgagattc ccaagaaggt ccggaaagag 660 gctctgctgc tcctgtcctg gaagcagatgctggatcatt tccaggccac gccccaccat 720 ggggtctact ctcgggagga ggagctgctgagggagcgga aacgcctggg ggtcttcggc 780 atcacctcct acgacttcca cagcgagagtggcctcttcc tcttccaggc cagcaacagc 840 ctcttccact gccgcgacgg cggcaagaacggcttcatgg tgtcccctat gaaaccgctg 900 gaaatcaaga cccagtgctc agggccccggatggacccca aaatctgccc tgccgaccct 960 gccttcttct ccttcatcaa taacagcgacctgtgggtgg ccaacatcga gacaggcgag 1020 gagcggcggc tgaccttctg ccaccaaggtttatccaatg tcctggatga ccccaagtct 1080 gcgggtgtgg ccaccttcgt catacaggaagagttcgacc gcttcactgg gtactggtgg 1140 tgccccacag cctcctggga aggttcagagggcctcaaga cgctgcgaat cctgtatgag 1200 gaagtcgatg agtccgaggt ggaggtcattcacgtcccct ctcctgcgct agaagaaagg 1260 aagacggact cgtatcggta ccccaggacaggcagcaaga atcccaagat tgccttgaaa 1320 ctggctgagt tccagactga cagccagggcaagatcgtct cgacccagga gaaggagctg 1380 gtgcagccct tcagctcgct gttcccgaaggtggagtaca tcgccagggc cgggtggacc 1440 cgggatggca aatacgcctg ggccatgttcctggaccggc cccagcagtg gctccagctc 1500 gtcctcctcc ccccggccct gttcatcccgagcacagaga atgaggagca gcggctagcc 1560 tctgccagag ctgtccccag gaatgtccagccgtatgtgg tgtacgagga ggtcaccaac 1620 gtctggatca atgttcatga catcttctatcccttccccc aatcagaggg agaggacgag 1680 ctctgctttc tccgcgccaa tgaatgcaagaccggcttct gccatttgta caaagtcacc 1740 gccgttttaa aatcccaggg ctacgattggagtgagccct tcagccccgg ggaagatgaa 1800 tttaagtgcc ccattaagga agagattgctctgaccagcg gtgaatggga ggttttggcg 1860 aggcacggct ccaagatctg ggtcaatgaggagaccaagc tggtgtactt ccagggcacc 1920 aaggacacgc cgctggagca ccacctctacgtggtcagct atgaggcggc cggcgagatc 1980 gtacgcctca ccacgcccgg cttctcccatagctgctcca tgagccagaa cttcgacatg 2040 ttcgtcagcc actacagcag cgtgagcacgccgccctgcg tgcacgtcta caagctgagc 2100 ggccccgacg acgaccccct gcacaagcagccccgcttct gggctagcat gatggaggca 2160 gccagctgcc ccccggatta tgttcctccagagatcttcc atttccacac gcgctcggat 2220 gtgcggctct acggcatgat ctacaagccccacgccttgc agccagggaa gaagcacccc 2280 accgtcctct ttgtatatgg aggcccccaggtgcagctgg tgaataactc cttcaaaggc 2340 atcaagtact tgcggctcaa cacactggcctccctgggct acgccgtggt tgtgattgac 2400 ggcaggggct cctgtcagcg agggcttcggttcgaagggg ccctgaaaaa ccaaatgggc 2460 caggtggaga tcgaggacca ggtggagggcctgcagttcg tggccgagaa gtatggcttc 2520 atcgacctga gccgagttgc catccatggctggtcctacg ggggcttcct ctcgctcatg 2580 gggctaatcc acaagcccca ggtgttcaaggtggccatcg cgggtgcccc ggtcaccgtc 2640 tggatggcct acgacacagg gtacactgagcgctacatgg acgtccctga gaacaaccag 2700 cacggctatg aggcgggttc cgtggccctgcacgtggaga agctgcccaa tgagcccaac 2760 cgcttgctta tcctccacgg cttcctggacgaaaacgtgc actttttcca cacaaacttc 2820 ctcgtctccc aactgatccg agcagggaaaccttaccagc tccagatcta ccccaacgag 2880 agacacagta ttcgctgccc cgagtcgggcgagcactatg aagtcacgtt gctgcacttt 2940 ctacaggaat acctctgagc ctgcccaccgggagccgcca catcacagca caagtggctg 3000 cagcctccgc ggggaaccag gcgggagggactgagtggcc cgcgggcccc agtgaggcac 3060 tttgtcccgc ccagcgctgg ccagccccgaggagccgctg ccttcaccgc cccgacgcct 3120 tttatccttt tttaaacgct cttgggttttatgtccgctg cttcttggtt gccgagacag 3180 agagatggtg gtctcgggcc agcccctcctctccccgcct tctgggagga ggaggtcaca 3240 cgctgatggg cactggagag gccagaagagactcagagga gcgggctgcc ttccgcctgg 3300 ggctccctgt gacctctcag tcccctggcccggccagcca ccgtccccag cacccaagca 3360 tgcaattgcc tgtccccccc ggccagcctccccaacttga tgtttgtgtt ttgtttgggg 3420 ggatattttt cataattatt taaaagacaggccgggcgcg gtggctcacg tctgtaatcc 3480 cagcactttg ggaggctgag gcgggcggatcacctgaggt tgggagttca agaccagcct 3540 ggccaacatg gggaaacccc gtctctactaaaaatacaaa aaattagccg ggtgtggtgg 3600 cgcgtgccta taatcccagc tactcgggaggctgaggcag gagaatcgct tgaacccggg 3660 aggtggaggt tgcggtgagc caagatcgcaccattgcact ccagcctggg caacaagagc 3720 gaaactctgt ctcaaaataa ataaaaaataaaagacagaa agcaaggggt gcctaaatct 3780 agacttgggg tccacaccgg gcagcggggttgcaacccag cacctggtag gctccatttc 3840 ttcccaagcc cgagcagagg gtcatgcgggccccacagga gaagcggcca gggcccgcgg 3900 ggggcaccac ctgtggacag ccctcctgtccccaagcttt caggcaggca ctgaaacgca 3960 ccgaacttcc acgctctgct ggtcagtggcggctgtcccc tccccagccc agccgcccag 4020 ccacatgtgt ctgcctgacc cgtacacaccaggggttccg gggttgggag ctgaaccatc 4080 cccacctcag ggttatattt ccctctccccttccctcccc gccaagagct ctgccagggg 4140 cgggcaaaaa aaaaagtaaa aagaaaagaaaaaaaaaaaa aagaaacaaa ccacctctac 4200 atattatgga aagaaaatat ttttgtcgattcttattctt ttataattat gcgtggaaga 4260 agtagacaca ttaaacgatt ccagttggaaacatgtcacc tg 4302 25 518 PRT Homo sapiens 25 Met Arg Lys Val Lys LysLeu Arg Leu Asp Lys Glu Asn Thr Gly Ser 1 5 10 15 Trp Arg Ser Phe SerLeu Asn Ser Glu Gly Ala Glu Arg Met Ala Thr 20 25 30 Thr Gly Thr Pro ThrAla Asp Arg Gly Asp Ala Ala Ala Thr Asp Asp 35 40 45 Pro Ala Ala Arg PheGln Val Gln Lys His Ser Trp Asp Gly Leu Arg 50 55 60 Ser Ile Ile His GlySer Arg Lys Tyr Ser Gly Leu Ile Val Asn Lys 65 70 75 80 Ala Pro His AspPhe Gln Phe Val Gln Lys Thr Asp Glu Ser Gly Pro 85 90 95 His Ser His ArgLeu Tyr Tyr Leu Gly Met Pro Tyr Gly Ser Arg Glu 100 105 110 Asn Ser LeuLeu Tyr Ser Glu Ile Pro Lys Lys Val Arg Lys Glu Ala 115 120 125 Leu LeuLeu Leu Ser Trp Lys Gln Met Leu Asp His Phe Gln Ala Thr 130 135 140 ProHis His Gly Val Tyr Ser Arg Glu Glu Glu Leu Leu Arg Glu Arg 145 150 155160 Lys Arg Leu Gly Val Phe Gly Ile Thr Ser Tyr Asp Phe His Ser Glu 165170 175 Ser Gly Leu Phe Leu Phe Gln Ala Ser Asn Ser Leu Phe His Cys Arg180 185 190 Asp Gly Gly Lys Asn Gly Phe Met Val Ser Pro Met Lys Pro LeuGlu 195 200 205 Ile Lys Thr Gln Cys Ser Gly Pro Arg Met Asp Pro Lys IleCys Pro 210 215 220 Ala Asp Pro Ala Phe Phe Ser Phe Ile Asn Asn Ser AspLeu Trp Val 225 230 235 240 Ala Asn Ile Glu Thr Gly Glu Glu Arg Arg LeuThr Phe Cys His Gln 245 250 255 Gly Leu Ser Asn Val Leu Asp Asp Pro LysSer Ala Gly Val Ala Thr 260 265 270 Phe Val Ile Gln Glu Glu Phe Asp ArgPhe Thr Gly Tyr Trp Trp Cys 275 280 285 Pro Thr Ala Ser Trp Glu Gly SerGlu Gly Leu Lys Thr Leu Arg Ile 290 295 300 Leu Tyr Glu Glu Val Asp GluSer Glu Val Glu Val Ile His Val Pro 305 310 315 320 Ser Pro Ala Leu GluGlu Arg Lys Thr Asp Ser Tyr Arg Tyr Pro Arg 325 330 335 Thr Gly Ser LysAsn Pro Lys Ile Ala Leu Lys Leu Ala Glu Phe Gln 340 345 350 Thr Asp SerGln Gly Lys Ile Val Ser Thr Gln Glu Lys Glu Leu Val 355 360 365 Gln ProPhe Ser Ser Leu Phe Pro Lys Val Glu Tyr Ile Ala Arg Ala 370 375 380 GlyTrp Thr Arg Asp Gly Lys Tyr Ala Trp Ala Met Phe Leu Asp Arg 385 390 395400 Pro Gln Gln Trp Leu Gln Leu Val Leu Leu Pro Pro Ala Leu Phe Ile 405410 415 Pro Ser Thr Glu Asn Glu Glu Gln Arg Leu Ala Ser Ala Arg Ala Val420 425 430 Pro Arg Asn Val Gln Pro Tyr Val Val Tyr Glu Glu Val Thr AsnVal 435 440 445 Trp Ile Asn Val His Asp Ile Phe Tyr Pro Phe Pro Gln SerGlu Gly 450 455 460 Glu Asp Glu Leu Cys Phe Leu Arg Ala Asn Glu Cys LysThr Gly Phe 465 470 475 480 Cys His Leu Tyr Lys Val Thr Ala Val Leu LysSer Gln Gly Tyr Asp 485 490 495 Trp Ser Glu Pro Phe Ser Pro Gly Glu GlyGlu Gln Ser Leu Thr Asn 500 505 510 Ala Val Asp Ser Ser Arg 515 26 2411DNA Homo sapiens 26 caggccgccg cctgggtcgc tcaacttccg ggtcaaaggtgcctgagccg gcgggtcccc 60 tgtgtccgcc gcggctgtcg tcccccgctc ccgccacttccggggtcgca gtcccgggca 120 tggagccgcg accgtgaggc gccgctggac ccgggacgacctgcccagtc cggccgccgc 180 cccacgtccc ggtctgtgtc ccacgcctgc agctggaatggaggctctct ggacccttta 240 gaaggcaccc ctgccctcct gaggtcagct gagcggttaatgcggaaggt taagaaactg 300 cgcctggaca aggagaacac cggaagttgg agaagcttctcgctgaattc cgagggggct 360 gagaggatgg ccaccaccgg gaccccaacg gccgaccgaggcgacgcagc cgccacagat 420 gacccggccg cccgcttcca ggtgcagaag cactcgtgggacgggctccg gagcatcatc 480 cacggcagcc gcaagtactc gggcctcatt gtcaacaaggcgccccacga cttccagttt 540 gtgcagaaga cggatgagtc tgggccccac tcccaccgcctctactacct gggaatgcca 600 tatggcagcc gagagaactc cctcctctac tctgagattcccaagaaggt ccggaaagag 660 gctctgctgc tcctgtcctg gaagcagatg ctggatcatttccaggccac gccccaccat 720 ggggtctact ctcgggagga ggagctgctg agggagcggaaacgcctggg ggtcttcggc 780 atcacctcct acgacttcca cagcgagagt ggcctcttcctcttccaggc cagcaacagc 840 ctcttccact gccgcgacgg cggcaagaac ggcttcatggtgtcccctat gaaaccgctg 900 gaaatcaaga cccagtgctc agggccccgg atggaccccaaaatctgccc tgccgaccct 960 gccttcttct ccttcatcaa taacagcgac ctgtgggtggccaacatcga gacaggcgag 1020 gagcggcggc tgaccttctg ccaccaaggt ttatccaatgtcctggatga ccccaagtct 1080 gcgggtgtgg ccaccttcgt catacaggaa gagttcgaccgcttcactgg gtactggtgg 1140 tgccccacag cctcctggga aggttcagag ggcctcaagacgctgcgaat cctgtatgag 1200 gaagtcgatg agtccgaggt ggaggtcatt cacgtcccctctcctgcgct agaagaaagg 1260 aagacggact cgtatcggta ccccaggaca ggcagcaagaatcccaagat tgccttgaaa 1320 ctggctgagt tccagactga cagccagggc aagatcgtctcgacccagga gaaggagctg 1380 gtgcagccct tcagctcgct gttcccgaag gtggagtacatcgccagggc cgggtggacc 1440 cgggatggca aatacgcctg ggccatgttc ctggaccggccccagcagtg gctccagctc 1500 gtcctcctcc ccccggccct gttcatcccg agcacagagaatgaggagca gcggctagcc 1560 tctgccagag ctgtccccag gaatgtccag ccgtatgtggtgtacgagga ggtcaccaac 1620 gtctggatca atgttcatga catcttctat cccttcccccaatcagaggg agaggacgag 1680 ctctgctttc tccgcgccaa tgaatgcaag accggcttctgccatttgta caaagtcacc 1740 gccgttttaa aatcccaggg ctacgattgg agtgagcccttcagccccgg ggaaggtgag 1800 cagagcctga cgaatgctgt cgactcatcg cgttagtcacgtgtggttca atatgctgtt 1860 tgttcattgg tcggcccccc cactcagcca gcacaccctgcgggagaagg aacagggatc 1920 ggcaggaagc cagccttccc cagtgactgc atgatctggcagggcttaga gcacccaact 1980 gttggcttat tcaggcagca gatttactga gcacctcccctgtgccaggc ccttagcaca 2040 accaggggtt ggccacctac ggcccacagg tcaaatccggcccaccacct gtgttcataa 2100 ataaagtttt attggcactg agccacagcc acttgtttacagagactgtc tgtggtcgct 2160 tttgtgctgc agcagcagaa ctgggtagtc ccagcagaaactgttgtgca aggccaagat 2220 ttactgtcta gccctttgta gaaacatttg ccagctcctgctgtaggtag ctgtgatgga 2280 attgttcact gtaaataaag aaaaaggaaa atccctgctcttgggacctt ctagtggagg 2340 aggcagtatt ccagaaacag ttagaggtgc tgcctctggtgtgctgtggg tggcagatgc 2400 agatcctagt c 2411 27 892 PRT Homo sapiens 27Met Arg Lys Val Lys Lys Leu Arg Leu Asp Lys Glu Asn Thr Gly Ser 1 5 1015 Trp Arg Ser Phe Ser Leu Asn Ser Glu Gly Ala Glu Arg Met Ala Thr 20 2530 Thr Gly Thr Pro Thr Ala Asp Arg Gly Asp Ala Ala Ala Thr Asp Asp 35 4045 Pro Ala Ala Arg Phe Gln Val Gln Lys His Ser Trp Asp Gly Leu Arg 50 5560 Ser Ile Ile His Gly Ser Arg Lys Tyr Ser Gly Leu Ile Val Asn Lys 65 7075 80 Ala Pro His Asp Phe Gln Phe Val Gln Lys Thr Asp Glu Ser Gly Pro 8590 95 His Ser His Arg Leu Tyr Tyr Leu Gly Met Pro Tyr Gly Ser Arg Glu100 105 110 Asn Ser Leu Leu Tyr Ser Glu Ile Pro Lys Lys Val Arg Lys GluAla 115 120 125 Leu Leu Leu Leu Ser Trp Lys Gln Met Leu Asp His Phe GlnAla Thr 130 135 140 Pro His His Gly Val Tyr Ser Arg Glu Glu Glu Leu LeuArg Glu Arg 145 150 155 160 Lys Arg Leu Gly Val Phe Gly Ile Thr Ser TyrAsp Phe His Ser Glu 165 170 175 Ser Gly Leu Phe Leu Phe Gln Ala Ser AsnSer Leu Phe His Cys Arg 180 185 190 Asp Gly Gly Lys Asn Gly Phe Met ValSer Pro Met Lys Pro Leu Glu 195 200 205 Ile Lys Thr Gln Cys Ser Gly ProArg Met Asp Pro Lys Ile Cys Pro 210 215 220 Ala Asp Pro Ala Phe Phe SerPhe Ile Asn Asn Ser Asp Leu Trp Val 225 230 235 240 Ala Asn Ile Glu ThrGly Glu Glu Arg Arg Leu Thr Phe Cys His Gln 245 250 255 Gly Leu Ser AsnVal Leu Asp Asp Pro Lys Ser Ala Gly Val Ala Thr 260 265 270 Phe Val IleGln Glu Glu Phe Asp Arg Phe Thr Gly Tyr Trp Trp Cys 275 280 285 Pro ThrAla Ser Trp Glu Gly Ser Glu Gly Leu Lys Thr Leu Arg Ile 290 295 300 LeuTyr Glu Glu Val Asp Glu Ser Glu Val Glu Val Ile His Val Pro 305 310 315320 Ser Pro Ala Leu Glu Glu Arg Lys Thr Asp Ser Tyr Arg Tyr Pro Arg 325330 335 Thr Gly Ser Lys Asn Pro Lys Ile Ala Leu Lys Leu Ala Glu Phe Gln340 345 350 Thr Asp Ser Gln Gly Lys Ile Val Ser Thr Gln Glu Lys Glu LeuVal 355 360 365 Gln Pro Phe Ser Ser Leu Phe Pro Lys Val Glu Tyr Ile AlaArg Ala 370 375 380 Gly Trp Thr Arg Asp Gly Lys Tyr Ala Trp Ala Met PheLeu Asp Arg 385 390 395 400 Pro Gln Gln Trp Leu Gln Leu Val Leu Leu ProPro Ala Leu Phe Ile 405 410 415 Pro Ser Thr Glu Asn Glu Glu Gln Arg LeuAla Ser Ala Arg Ala Val 420 425 430 Pro Arg Asn Val Gln Pro Tyr Val ValTyr Glu Glu Val Thr Asn Val 435 440 445 Trp Ile Asn Val His Asp Ile PheTyr Pro Phe Pro Gln Ser Glu Gly 450 455 460 Glu Asp Glu Leu Cys Phe LeuArg Ala Asn Glu Cys Lys Thr Gly Phe 465 470 475 480 Cys His Leu Tyr LysVal Thr Ala Val Leu Lys Ser Gln Gly Tyr Asp 485 490 495 Trp Ser Glu ProPhe Ser Pro Gly Glu Asp Glu Phe Lys Cys Pro Ile 500 505 510 Lys Glu GluIle Ala Leu Thr Ser Gly Glu Trp Glu Val Leu Ala Arg 515 520 525 His GlySer Lys Ile Trp Val Asn Glu Glu Thr Lys Leu Val Tyr Phe 530 535 540 GlnGly Thr Lys Asp Thr Pro Leu Glu His His Leu Tyr Val Val Ser 545 550 555560 Tyr Glu Ala Ala Gly Glu Ile Val Arg Leu Thr Thr Pro Gly Phe Ser 565570 575 His Ser Cys Ser Met Ser Gln Asn Phe Asp Met Phe Val Ser His Tyr580 585 590 Ser Ser Val Ser Thr Pro Pro Cys Val His Val Tyr Lys Leu SerGly 595 600 605 Pro Asp Asp Asp Pro Leu His Lys Gln Pro Arg Phe Trp AlaSer Met 610 615 620 Met Glu Ala Ala Ser Cys Pro Pro Asp Tyr Val Pro ProGlu Ile Phe 625 630 635 640 His Phe His Thr Arg Ser Asp Val Arg Leu TyrGly Met Ile Tyr Lys 645 650 655 Pro His Ala Leu Gln Pro Gly Lys Lys HisPro Thr Val Leu Phe Val 660 665 670 Tyr Gly Gly Pro Gln Val Gln Leu ValAsn Asn Ser Phe Lys Gly Ile 675 680 685 Lys Tyr Leu Arg Leu Asn Thr LeuAla Ser Leu Gly Tyr Ala Val Val 690 695 700 Val Ile Asp Gly Arg Gly SerCys Gln Arg Gly Leu Arg Phe Glu Gly 705 710 715 720 Ala Leu Lys Asn GlnMet Gly Gln Val Glu Ile Glu Asp Gln Val Glu 725 730 735 Gly Leu Gln PheVal Ala Glu Lys Tyr Gly Phe Ile Asp Leu Ser Arg 740 745 750 Val Ala IleHis Gly Trp Ser Tyr Gly Gly Phe Leu Ser Leu Met Gly 755 760 765 Leu IleHis Lys Pro Gln Val Phe Lys Val Ala Ile Ala Gly Ala Pro 770 775 780 ValThr Val Trp Met Ala Tyr Asp Thr Gly Tyr Thr Glu Arg Tyr Met 785 790 795800 Asp Val Pro Glu Asn Asn Gln His Gly Tyr Glu Ala Gly Ser Val Ala 805810 815 Leu His Val Glu Lys Leu Pro Asn Glu Pro Asn Arg Leu Leu Ile Leu820 825 830 His Gly Phe Leu Asp Glu Asn Val His Phe Phe His Thr Asn PheLeu 835 840 845 Val Ser Gln Leu Ile Arg Ala Gly Lys Pro Tyr Gln Leu GlnIle Tyr 850 855 860 Pro Asn Glu Arg His Ser Ile Arg Cys Pro Glu Ser GlyGlu His Tyr 865 870 875 880 Glu Val Thr Leu Leu His Phe Leu Gln Glu TyrLeu 885 890 28 4219 DNA Homo sapiens 28 caggccgccg cctgggtcgc tcaacttccgggtcaaaggt gcctgagccg gcgggtcccc 60 tgtgtccgcc gcggctgtcg tcccccgctcccgccacttc cggggtcgca gtcccgggca 120 tggagccgcg accgtgaggc gccgctggacccgggacgac ctgcccagtc cggccgccgc 180 cccacgtccc ggtctgtgtc ccacgcctgcagctggaatg gaggctctct ggacccttta 240 gaaggcaccc ctgccctcct gaggtcagctgagcggttaa tgcggaaggt taagaaactg 300 cgcctggaca aggagaacac cggaagttggagaagcttct cgctgaattc cgagggggct 360 gagaggatgg ccaccaccgg gaccccaacggccgaccgag gcgacgcagc cgccacagat 420 gacccggccg cccgcttcca ggtgcagaagcactcgtggg acgggctccg gagcatcatc 480 cacggcagcc gcaagtactc gggcctcattgtcaacaagg cgccccacga cttccagttt 540 gtgcagaaga cggatgagtc tgggccccactcccaccgcc tctactacct gggaatgcca 600 tatggcagcc gagagaactc cctcctctactctgagattc ccaagaaggt ccggaaagag 660 gctctgctgc tcctgtcctg gaagcagatgctggatcatt tccaggccac gccccaccat 720 ggggtctact ctcgggagga ggagctgctgagggagcgga aacgcctggg ggtcttcggc 780 atcacctcct acgacttcca cagcgagagtggcctcttcc tcttccaggc cagcaacagc 840 ctcttccact gccgcgacgg cggcaagaacggcttcatgg tgtcccctat gaaaccgctg 900 gaaatcaaga cccagtgctc agggccccggatggacccca aaatctgccc tgccgaccct 960 gccttcttct ccttcatcaa taacagcgacctgtgggtgg ccaacatcga gacaggcgag 1020 gagcggcggc tgaccttctg ccaccaaggtttatccaatg tcctggatga ccccaagtct 1080 gcgggtgtgg ccaccttcgt catacaggaagagttcgacc gcttcactgg gtactggtgg 1140 tgccccacag cctcctggga aggttcagagggcctcaaga cgctgcgaat cctgtatgag 1200 gaagtcgatg agtccgaggt ggaggtcattcacgtcccct ctcctgcgct agaagaaagg 1260 aagacggact cgtatcggta ccccaggacaggcagcaaga atcccaagat tgccttgaaa 1320 ctggctgagt tccagactga cagccagggcaagatcgtct cgacccagga gaaggagctg 1380 gtgcagccct tcagctcgct gttcccgaaggtggagtaca tcgccagggc cgggtggacc 1440 cgggatggca aatacgcctg ggccatgttcctggaccggc cccagcagtg gctccagctc 1500 gtcctcctcc ccccggccct gttcatcccgagcacagaga atgaggagca gcggctagcc 1560 tctgccagag ctgtccccag gaatgtccagccgtatgtgg tgtacgagga ggtcaccaac 1620 gtctggatca atgttcatga catcttctatcccttccccc aatcagaggg agaggacgag 1680 ctctgctttc tccgcgccaa tgaatgcaagaccggcttct gccatttgta caaagtcacc 1740 gccgttttaa aatcccaggg ctacgattggagtgagccct tcagccccgg ggaagatgaa 1800 tttaagtgcc ccattaagga agagattgctctgaccagcg gtgaatggga ggttttggcg 1860 aggcacggct ccaagatctg ggtcaatgaggagaccaagc tggtgtactt ccagggcacc 1920 aaggacacgc cgctggagca ccacctctacgtggtcagct atgaggcggc cggcgagatc 1980 gtacgcctca ccacgcccgg cttctcccatagctgctcca tgagccagaa cttcgacatg 2040 ttcgtcagcc actacagcag cgtgagcacgccgccctgcg tgcacgtcta caagctgagc 2100 ggccccgacg acgaccccct gcacaagcagccccgcttct gggctagcat gatggaggca 2160 gccagctgcc ccccggatta tgttcctccagagatcttcc atttccacac gcgctcggat 2220 gtgcggctct acggcatgat ctacaagccccacgccttgc agccagggaa gaagcacccc 2280 accgtcctct ttgtatatgg aggcccccaggtgcagctgg tgaataactc cttcaaaggc 2340 atcaagtact tgcggctcaa cacactggcctccctgggct acgccgtggt tgtgattgac 2400 ggcaggggct cctgtcagcg agggcttcggttcgaagggg ccctgaaaaa ccaaatgggc 2460 caggtggaga tcgaggacca ggtggagggcctgcagttcg tggccgagaa gtatggcttc 2520 atcgacctga gccgagttgc catccatggctggtcctacg ggggcttcct ctcgctcatg 2580 gggctaatcc acaagcccca ggtgttcaaggtggccatcg cgggtgcccc ggtcaccgtc 2640 tggatggcct acgacacagg gtacactgagcgctacatgg acgtccctga gaacaaccag 2700 cacggctatg aggcgggttc cgtggccctgcacgtggaga agctgcccaa tgagcccaac 2760 cgcttgctta tcctccacgg cttcctggacgaaaacgtgc actttttcca cacaaacttc 2820 ctcgtctccc aactgatccg agcagggaaaccttaccagc tccagatcta ccccaacgag 2880 agacacagta ttcgctgccc cgagtcgggcgagcactatg aagtcacgtt gctgcacttt 2940 ctacaggaat acctctgagc ctgcccaccgggagccgcca catcacagca caagtggctg 3000 cagcctccgc ggggaaccag gcgggagggactgagtggcc cgcgggcccc agtgaggcac 3060 tttgtcccgc ccagcgctgg ccagccccgaggagccgctg ccttcaccgc cccgacgcct 3120 tttatccttt tttaaacgct cttgggttttatgtccgctg cttcttggtt gccgagacag 3180 agagatggtg gtctcgggcc agcccctcctctccccgcct tctgggagga ggaggtcaca 3240 cgctgatggg cactggagag gccagaagagactcagagga gcgggctgcc ttccgcctgg 3300 ggctccctgt gacctctcag tcccctggcccggccagcca ccgtccccag cacccaagca 3360 tgcaattgcc tgtccccccc ggccagcctccccaacttga tgtttgtgtt ttgtttgggg 3420 ggatattttt cataattatt taaaagacaggccgggcgcg gtggctcacg tctgtaatcc 3480 cagcactttg ggaggctgag gcgggcggatcacctgaggt tgggagttca agaccagcct 3540 ggccaacatg gggaaacccc gtctctactaaaaatacaaa aaattagccg ggtgtggtgg 3600 cgcgtgccta taatcccagc tactcgggaggctgaggcag gagaatcgct tgaacccggg 3660 aggtggaggt tgcggtgagc caagatcgcaccattgcact ccagcctggg caacaagagc 3720 gaaactctgt ctcaaaataa ataaaaaataaaagacagaa agcaaggggt gcctaaatct 3780 agacttgggg tccacaccgg gcagcggggttgcaacccag cacctggtag gctccatttc 3840 ttcccaagcc cgactttcag gcaggcactgaaacgcaccg aacttccacg ctctgctggt 3900 cagtggcggc tgtcccctcc ccagcccagccgcccagcca catgtgtctg cctgacccgt 3960 acacaccagg ggttccgggg ttgggagctgaaccatcccc acctcagggt tatatttccc 4020 tctccccttc cctccccgcc aagagctctgccaggggcgg gcaaaaaaaa aagtaaaaag 4080 aaaagaaaaa aaaaaaaaag aaacaaaccacctctacata ttatggaaag aaaatatttt 4140 tgtcgattct tattctttta taattatgcgtggaagaagt agacacatta aacgattcca 4200 gttggaaaca tgtcacctg 4219 29 832PRT Homo sapiens 29 Met Arg Lys Val Lys Lys Leu Arg Leu Asp Lys Glu AsnThr Gly Ser 1 5 10 15 Trp Arg Ser Phe Ser Leu Asn Ser Glu Gly Ala GluArg Met Ala Thr 20 25 30 Thr Gly Thr Pro Thr Ala Asp Arg Gly Asp Ala AlaAla Thr Asp Asp 35 40 45 Pro Ala Ala Arg Phe Gln Val Gln Lys His Ser TrpAsp Gly Leu Arg 50 55 60 Ser Ile Ile His Gly Ser Arg Lys Tyr Ser Gly LeuIle Val Asn Lys 65 70 75 80 Ala Pro His Asp Phe Gln Phe Val Gln Lys ThrAsp Glu Ser Gly Pro 85 90 95 His Ser His Arg Leu Tyr Tyr Leu Gly Met ProTyr Gly Ser Arg Glu 100 105 110 Asn Ser Leu Leu Tyr Ser Glu Ile Pro LysLys Val Arg Lys Glu Ala 115 120 125 Leu Leu Leu Leu Ser Trp Lys Gln MetLeu Asp His Phe Gln Ala Thr 130 135 140 Pro His His Gly Val Tyr Ser ArgGlu Glu Glu Leu Leu Arg Glu Arg 145 150 155 160 Lys Arg Leu Gly Val PheGly Ile Thr Ser Tyr Asp Phe His Ser Glu 165 170 175 Ser Gly Leu Phe LeuPhe Gln Ala Ser Asn Ser Leu Phe His Cys Arg 180 185 190 Asp Gly Gly LysAsn Gly Phe Met Val Ser Pro Met Lys Pro Leu Glu 195 200 205 Ile Lys ThrGln Cys Ser Gly Pro Arg Met Asp Pro Lys Ile Cys Pro 210 215 220 Ala AspPro Ala Phe Phe Ser Phe Ile Asn Asn Ser Asp Leu Trp Val 225 230 235 240Ala Asn Ile Glu Thr Gly Glu Glu Arg Arg Leu Thr Phe Cys His Gln 245 250255 Gly Leu Ser Asn Val Leu Asp Asp Pro Lys Ser Ala Gly Val Ala Thr 260265 270 Phe Val Ile Gln Glu Glu Phe Asp Arg Phe Thr Gly Tyr Trp Trp Cys275 280 285 Pro Thr Ala Ser Trp Glu Gly Ser Glu Gly Leu Lys Thr Leu ArgIle 290 295 300 Leu Tyr Glu Glu Val Asp Glu Ser Glu Val Glu Val Ile HisVal Pro 305 310 315 320 Ser Pro Ala Leu Glu Glu Arg Lys Thr Asp Ser TyrArg Tyr Pro Arg 325 330 335 Thr Gly Ser Lys Asn Pro Lys Ile Ala Leu LysLeu Ala Glu Phe Gln 340 345 350 Thr Asp Ser Gln Gly Lys Ile Val Ser ThrGln Glu Lys Glu Leu Val 355 360 365 Gln Pro Phe Ser Ser Leu Phe Pro LysVal Glu Tyr Ile Ala Arg Ala 370 375 380 Gly Trp Thr Arg Asp Gly Lys TyrAla Trp Ala Met Phe Leu Asp Arg 385 390 395 400 Pro Gln Gln Trp Leu GlnLeu Val Leu Leu Pro Pro Ala Leu Phe Ile 405 410 415 Pro Ser Thr Glu AsnGlu Glu Gln Arg Leu Ala Ser Ala Arg Ala Val 420 425 430 Pro Arg Asn ValGln Pro Tyr Val Val Tyr Glu Glu Val Thr Asn Val 435 440 445 Trp Ile AsnVal His Asp Ile Phe Tyr Pro Phe Pro Gln Ser Glu Gly 450 455 460 Glu AspGlu Leu Cys Phe Leu Arg Ala Asn Glu Cys Lys Thr Gly Phe 465 470 475 480Cys His Leu Tyr Lys Val Thr Ala Val Leu Lys Ser Gln Gly Tyr Asp 485 490495 Trp Ser Glu Pro Phe Ser Pro Gly Glu Asp Glu Phe Lys Cys Pro Ile 500505 510 Lys Glu Glu Ile Ala Leu Thr Ser Gly Glu Trp Glu Val Leu Ala Arg515 520 525 His Gly Ser Lys Ile Trp Val Asn Glu Glu Thr Lys Leu Val TyrPhe 530 535 540 Gln Gly Thr Lys Asp Thr Pro Leu Glu His His Leu Tyr ValVal Ser 545 550 555 560 Tyr Glu Ala Ala Gly Glu Ile Val Arg Leu Thr ThrPro Gly Phe Ser 565 570 575 His Ser Cys Ser Met Ser Gln Asn Phe Asp MetPhe Val Ser His Tyr 580 585 590 Ser Ser Val Ser Thr Pro Pro Cys Val HisVal Tyr Lys Leu Ser Gly 595 600 605 Pro Asp Asp Asp Pro Leu His Lys GlnPro Arg Phe Trp Ala Ser Met 610 615 620 Met Glu Ala Ala Ser Cys Pro ProAsp Tyr Val Pro Pro Glu Ile Phe 625 630 635 640 His Phe His Thr Arg SerAsp Val Arg Leu Tyr Gly Met Ile Tyr Lys 645 650 655 Pro His Ala Leu GlnPro Gly Lys Lys His Pro Thr Val Leu Phe Val 660 665 670 Tyr Gly Gly ProGln Val Gln Leu Val Asn Asn Ser Phe Lys Gly Ile 675 680 685 Lys Tyr LeuArg Leu Asn Thr Leu Ala Ser Leu Gly Tyr Ala Val Val 690 695 700 Val IleAsp Gly Arg Gly Ser Cys Gln Arg Gly Leu Arg Phe Glu Gly 705 710 715 720Ala Leu Lys Asn Gln Met Gly Gln Val Glu Ile Glu Asp Gln Val Glu 725 730735 Gly Leu Gln Phe Val Ala Glu Lys Tyr Gly Phe Ile Asp Leu Ser Arg 740745 750 Val Ala Ile His Gly Trp Ser Tyr Gly Gly Phe Leu Ser Leu Met Gly755 760 765 Leu Ile His Lys Pro Gln Val Phe Lys Ala Gln Pro Leu Ala TyrPro 770 775 780 Pro Arg Leu Pro Gly Arg Lys Arg Ala Leu Phe Pro His LysLeu Pro 785 790 795 800 Arg Leu Pro Thr Asp Pro Ser Arg Glu Thr Leu ProAla Pro Asp Leu 805 810 815 Pro Gln Arg Glu Thr Gln Tyr Ser Leu Pro ArgVal Gly Arg Ala Leu 820 825 830 30 4159 DNA Homo sapiens 30 caggccgccgcctgggtcgc tcaacttccg ggtcaaaggt gcctgagccg gcgggtcccc 60 tgtgtccgccgcggctgtcg tcccccgctc ccgccacttc cggggtcgca gtcccgggca 120 tggagccgcgaccgtgaggc gccgctggac ccgggacgac ctgcccagtc cggccgccgc 180 cccacgtcccggtctgtgtc ccacgcctgc agctggaatg gaggctctct ggacccttta 240 gaaggcacccctgccctcct gaggtcagct gagcggttaa tgcggaaggt taagaaactg 300 cgcctggacaaggagaacac cggaagttgg agaagcttct cgctgaattc cgagggggct 360 gagaggatggccaccaccgg gaccccaacg gccgaccgag gcgacgcagc cgccacagat 420 gacccggccgcccgcttcca ggtgcagaag cactcgtggg acgggctccg gagcatcatc 480 cacggcagccgcaagtactc gggcctcatt gtcaacaagg cgccccacga cttccagttt 540 gtgcagaagacggatgagtc tgggccccac tcccaccgcc tctactacct gggaatgcca 600 tatggcagccgagagaactc cctcctctac tctgagattc ccaagaaggt ccggaaagag 660 gctctgctgctcctgtcctg gaagcagatg ctggatcatt tccaggccac gccccaccat 720 ggggtctactctcgggagga ggagctgctg agggagcgga aacgcctggg ggtcttcggc 780 atcacctcctacgacttcca cagcgagagt ggcctcttcc tcttccaggc cagcaacagc 840 ctcttccactgccgcgacgg cggcaagaac ggcttcatgg tgtcccctat gaaaccgctg 900 gaaatcaagacccagtgctc agggccccgg atggacccca aaatctgccc tgccgaccct 960 gccttcttctccttcatcaa taacagcgac ctgtgggtgg ccaacatcga gacaggcgag 1020 gagcggcggctgaccttctg ccaccaaggt ttatccaatg tcctggatga ccccaagtct 1080 gcgggtgtggccaccttcgt catacaggaa gagttcgacc gcttcactgg gtactggtgg 1140 tgccccacagcctcctggga aggttcagag ggcctcaaga cgctgcgaat cctgtatgag 1200 gaagtcgatgagtccgaggt ggaggtcatt cacgtcccct ctcctgcgct agaagaaagg 1260 aagacggactcgtatcggta ccccaggaca ggcagcaaga atcccaagat tgccttgaaa 1320 ctggctgagttccagactga cagccagggc aagatcgtct cgacccagga gaaggagctg 1380 gtgcagcccttcagctcgct gttcccgaag gtggagtaca tcgccagggc cgggtggacc 1440 cgggatggcaaatacgcctg ggccatgttc ctggaccggc cccagcagtg gctccagctc 1500 gtcctcctccccccggccct gttcatcccg agcacagaga atgaggagca gcggctagcc 1560 tctgccagagctgtccccag gaatgtccag ccgtatgtgg tgtacgagga ggtcaccaac 1620 gtctggatcaatgttcatga catcttctat cccttccccc aatcagaggg agaggacgag 1680 ctctgctttctccgcgccaa tgaatgcaag accggcttct gccatttgta caaagtcacc 1740 gccgttttaaaatcccaggg ctacgattgg agtgagccct tcagccccgg ggaagatgaa 1800 tttaagtgccccattaagga agagattgct ctgaccagcg gtgaatggga ggttttggcg 1860 aggcacggctccaagatctg ggtcaatgag gagaccaagc tggtgtactt ccagggcacc 1920 aaggacacgccgctggagca ccacctctac gtggtcagct atgaggcggc cggcgagatc 1980 gtacgcctcaccacgcccgg cttctcccat agctgctcca tgagccagaa cttcgacatg 2040 ttcgtcagccactacagcag cgtgagcacg ccgccctgcg tgcacgtcta caagctgagc 2100 ggccccgacgacgaccccct gcacaagcag ccccgcttct gggctagcat gatggaggca 2160 gccagctgccccccggatta tgttcctcca gagatcttcc atttccacac gcgctcggat 2220 gtgcggctctacggcatgat ctacaagccc cacgccttgc agccagggaa gaagcacccc 2280 accgtcctctttgtatatgg aggcccccag gtgcagctgg tgaataactc cttcaaaggc 2340 atcaagtacttgcggctcaa cacactggcc tccctgggct acgccgtggt tgtgattgac 2400 ggcaggggctcctgtcagcg agggcttcgg ttcgaagggg ccctgaaaaa ccaaatgggc 2460 caggtggagatcgaggacca ggtggagggc ctgcagttcg tggccgagaa gtatggcttc 2520 atcgacctgagccgagttgc catccatggc tggtcctacg ggggcttcct ctcgctcatg 2580 gggctaatccacaagcccca ggtgttcaag gcccaaccgc ttgcttatcc tccacggctt 2640 cctggacgaaaacgtgcact ttttccacac aaacttcctc gtctcccaac tgatccgagc 2700 agggaaaccttaccagctcc agatctaccc caacgagaga cacagtattc gctgccccga 2760 gtcgggcgagcactatgaag tcacgttgct gcactttcta caggaatacc tctgagcctg 2820 cccaccgggagccgccacat cacagcacaa gtggctgcag cctccgcggg gaaccaggcg 2880 ggagggactgagtggcccgc gggccccagt gaggcacttt gtcccgccca gcgctggcca 2940 gccccgaggagccgctgcct tcaccgcccc gacgcctttt atcctttttt aaacgctctt 3000 gggttttatgtccgctgctt cttggttgcc gagacagaga gatggtggtc tcgggccagc 3060 ccctcctctccccgccttct gggaggagga ggtcacacgc tgatgggcac tggagaggcc 3120 agaagagactcagaggagcg ggctgccttc cgcctggggc tccctgtgac ctctcagtcc 3180 cctggcccggccagccaccg tccccagcac ccaagcatgc aattgcctgt cccccccggc 3240 cagcctccccaacttgatgt ttgtgttttg tttgggggga tatttttcat aattatttaa 3300 aagacaggccgggcgcggtg gctcacgtct gtaatcccag cactttggga ggctgaggcg 3360 ggcggatcacctgaggttgg gagttcaaga ccagcctggc caacatgggg aaaccccgtc 3420 tctactaaaaatacaaaaaa ttagccgggt gtggtggcgc gtgcctataa tcccagctac 3480 tcgggaggctgaggcaggag aatcgcttga acccgggagg tggaggttgc ggtgagccaa 3540 gatcgcaccattgcactcca gcctgggcaa caagagcgaa actctgtctc aaaataaata 3600 aaaaataaaagacagaaagc aaggggtgcc taaatctaga cttggggtcc acaccgggca 3660 gcggggttgcaacccagcac ctggtaggct ccatttcttc ccaagcccga gcagagggtc 3720 atgcgggccccacaggagaa gcggccaggg cccgcggggg gcaccacctg tggacagccc 3780 tcctgtccccaagctttcag gcaggcactg aaacgcaccg aacttccacg ctctgctggt 3840 cagtggcggctgtcccctcc ccagcccagc cgcccagcca catgtgtctg cctgacccgt 3900 acacaccaggggttccgggg ttgggagctg aaccatcccc acctcagggt tatatttccc 3960 tctccccttccctccccgcc aagagctctg ccaggggcgg gcaaaaaaaa aagtaaaaag 4020 aaaagaaaaaaaaaaaaaag aaacaaacca cctctacata ttatggaaag aaaatatttt 4080 tgtcgattcttattctttta taattatgcg tggaagaagt agacacatta aacgattcca 4140 gttggaaacatgtcacctg 4159 31 832 PRT Homo sapiens 31 Met Arg Lys Val Lys Lys LeuArg Leu Asp Lys Glu Asn Thr Gly Ser 1 5 10 15 Trp Arg Ser Phe Ser LeuAsn Ser Glu Gly Ala Glu Arg Met Ala Thr 20 25 30 Thr Gly Thr Pro Thr AlaAsp Arg Gly Asp Ala Ala Ala Thr Asp Asp 35 40 45 Pro Ala Ala Arg Phe GlnVal Gln Lys His Ser Trp Asp Gly Leu Arg 50 55 60 Ser Ile Ile His Gly SerArg Lys Tyr Ser Gly Leu Ile Val Asn Lys 65 70 75 80 Ala Pro His Asp PheGln Phe Val Gln Lys Thr Asp Glu Ser Gly Pro 85 90 95 His Ser His Arg LeuTyr Tyr Leu Gly Met Pro Tyr Gly Ser Arg Glu 100 105 110 Asn Ser Leu LeuTyr Ser Glu Ile Pro Lys Lys Val Arg Lys Glu Ala 115 120 125 Leu Leu LeuLeu Ser Trp Lys Gln Met Leu Asp His Phe Gln Ala Thr 130 135 140 Pro HisHis Gly Val Tyr Ser Arg Glu Glu Glu Leu Leu Arg Glu Arg 145 150 155 160Lys Arg Leu Gly Val Phe Gly Ile Thr Ser Tyr Asp Phe His Ser Glu 165 170175 Ser Gly Leu Phe Leu Phe Gln Ala Ser Asn Ser Leu Phe His Cys Arg 180185 190 Asp Gly Gly Lys Asn Gly Phe Met Val Ser Pro Met Lys Pro Leu Glu195 200 205 Ile Lys Thr Gln Cys Ser Gly Pro Arg Met Asp Pro Lys Ile CysPro 210 215 220 Ala Asp Pro Ala Phe Phe Ser Phe Ile Asn Asn Ser Asp LeuTrp Val 225 230 235 240 Ala Asn Ile Glu Thr Gly Glu Glu Arg Arg Leu ThrPhe Cys His Gln 245 250 255 Gly Leu Ser Asn Val Leu Asp Asp Pro Lys SerAla Gly Val Ala Thr 260 265 270 Phe Val Ile Gln Glu Glu Phe Asp Arg PheThr Gly Tyr Trp Trp Cys 275 280 285 Pro Thr Ala Ser Trp Glu Gly Ser GluGly Leu Lys Thr Leu Arg Ile 290 295 300 Leu Tyr Glu Glu Val Asp Glu SerGlu Val Glu Val Ile His Val Pro 305 310 315 320 Ser Pro Ala Leu Glu GluArg Lys Thr Asp Ser Tyr Arg Tyr Pro Arg 325 330 335 Thr Gly Ser Lys AsnPro Lys Ile Ala Leu Lys Leu Ala Glu Phe Gln 340 345 350 Thr Asp Ser GlnGly Lys Ile Val Ser Thr Gln Glu Lys Glu Leu Val 355 360 365 Gln Pro PheSer Ser Leu Phe Pro Lys Val Glu Tyr Ile Ala Arg Ala 370 375 380 Gly TrpThr Arg Asp Gly Lys Tyr Ala Trp Ala Met Phe Leu Asp Arg 385 390 395 400Pro Gln Gln Trp Leu Gln Leu Val Leu Leu Pro Pro Ala Leu Phe Ile 405 410415 Pro Ser Thr Glu Asn Glu Glu Gln Arg Leu Ala Ser Ala Arg Ala Val 420425 430 Pro Arg Asn Val Gln Pro Tyr Val Val Tyr Glu Glu Val Thr Asn Val435 440 445 Trp Ile Asn Val His Asp Ile Phe Tyr Pro Phe Pro Gln Ser GluGly 450 455 460 Glu Asp Glu Leu Cys Phe Leu Arg Ala Asn Glu Cys Lys ThrGly Phe 465 470 475 480 Cys His Leu Tyr Lys Val Thr Ala Val Leu Lys SerGln Gly Tyr Asp 485 490 495 Trp Ser Glu Pro Phe Ser Pro Gly Glu Asp GluPhe Lys Cys Pro Ile 500 505 510 Lys Glu Glu Ile Ala Leu Thr Ser Gly GluTrp Glu Val Leu Ala Arg 515 520 525 His Gly Ser Lys Ile Trp Val Asn GluGlu Thr Lys Leu Val Tyr Phe 530 535 540 Gln Gly Thr Lys Asp Thr Pro LeuGlu His His Leu Tyr Val Val Ser 545 550 555 560 Tyr Glu Ala Ala Gly GluIle Val Arg Leu Thr Thr Pro Gly Phe Ser 565 570 575 His Ser Cys Ser MetSer Gln Asn Phe Asp Met Phe Val Ser His Tyr 580 585 590 Ser Ser Val SerThr Pro Pro Cys Val His Val Tyr Lys Leu Ser Gly 595 600 605 Pro Asp AspAsp Pro Leu His Lys Gln Pro Arg Phe Trp Ala Ser Met 610 615 620 Met GluAla Ala Ser Cys Pro Pro Asp Tyr Val Pro Pro Glu Ile Phe 625 630 635 640His Phe His Thr Arg Ser Asp Val Arg Leu Tyr Gly Met Ile Tyr Lys 645 650655 Pro His Ala Leu Gln Pro Gly Lys Lys His Pro Thr Val Leu Phe Val 660665 670 Tyr Gly Gly Pro Gln Val Gln Leu Val Asn Asn Ser Phe Lys Gly Ile675 680 685 Lys Tyr Leu Arg Leu Asn Thr Leu Ala Ser Leu Gly Tyr Ala ValVal 690 695 700 Val Ile Asp Gly Arg Gly Ser Cys Gln Arg Gly Leu Arg PheGlu Gly 705 710 715 720 Ala Leu Lys Asn Gln Met Gly Gln Val Glu Ile GluAsp Gln Val Glu 725 730 735 Gly Leu Gln Phe Val Ala Glu Lys Tyr Gly PheIle Asp Leu Ser Arg 740 745 750 Val Ala Ile His Gly Trp Ser Tyr Gly GlyPhe Leu Ser Leu Met Gly 755 760 765 Leu Ile His Lys Pro Gln Val Phe LysAla Gln Pro Leu Ala Tyr Pro 770 775 780 Pro Arg Leu Pro Gly Arg Lys ArgAla Leu Phe Pro His Lys Leu Pro 785 790 795 800 Arg Leu Pro Thr Asp ProSer Arg Glu Thr Leu Pro Ala Pro Asp Leu 805 810 815 Pro Gln Arg Glu ThrGln Tyr Ser Leu Pro Arg Val Gly Arg Ala Leu 820 825 830 32 4076 DNA Homosapiens 32 caggccgccg cctgggtcgc tcaacttccg ggtcaaaggt gcctgagccggcgggtcccc 60 tgtgtccgcc gcggctgtcg tcccccgctc ccgccacttc cggggtcgcagtcccgggca 120 tggagccgcg accgtgaggc gccgctggac ccgggacgac ctgcccagtccggccgccgc 180 cccacgtccc ggtctgtgtc ccacgcctgc agctggaatg gaggctctctggacccttta 240 gaaggcaccc ctgccctcct gaggtcagct gagcggttaa tgcggaaggttaagaaactg 300 cgcctggaca aggagaacac cggaagttgg agaagcttct cgctgaattccgagggggct 360 gagaggatgg ccaccaccgg gaccccaacg gccgaccgag gcgacgcagccgccacagat 420 gacccggccg cccgcttcca ggtgcagaag cactcgtggg acgggctccggagcatcatc 480 cacggcagcc gcaagtactc gggcctcatt gtcaacaagg cgccccacgacttccagttt 540 gtgcagaaga cggatgagtc tgggccccac tcccaccgcc tctactacctgggaatgcca 600 tatggcagcc gagagaactc cctcctctac tctgagattc ccaagaaggtccggaaagag 660 gctctgctgc tcctgtcctg gaagcagatg ctggatcatt tccaggccacgccccaccat 720 ggggtctact ctcgggagga ggagctgctg agggagcgga aacgcctgggggtcttcggc 780 atcacctcct acgacttcca cagcgagagt ggcctcttcc tcttccaggccagcaacagc 840 ctcttccact gccgcgacgg cggcaagaac ggcttcatgg tgtcccctatgaaaccgctg 900 gaaatcaaga cccagtgctc agggccccgg atggacccca aaatctgccctgccgaccct 960 gccttcttct ccttcatcaa taacagcgac ctgtgggtgg ccaacatcgagacaggcgag 1020 gagcggcggc tgaccttctg ccaccaaggt ttatccaatg tcctggatgaccccaagtct 1080 gcgggtgtgg ccaccttcgt catacaggaa gagttcgacc gcttcactgggtactggtgg 1140 tgccccacag cctcctggga aggttcagag ggcctcaaga cgctgcgaatcctgtatgag 1200 gaagtcgatg agtccgaggt ggaggtcatt cacgtcccct ctcctgcgctagaagaaagg 1260 aagacggact cgtatcggta ccccaggaca ggcagcaaga atcccaagattgccttgaaa 1320 ctggctgagt tccagactga cagccagggc aagatcgtct cgacccaggagaaggagctg 1380 gtgcagccct tcagctcgct gttcccgaag gtggagtaca tcgccagggccgggtggacc 1440 cgggatggca aatacgcctg ggccatgttc ctggaccggc cccagcagtggctccagctc 1500 gtcctcctcc ccccggccct gttcatcccg agcacagaga atgaggagcagcggctagcc 1560 tctgccagag ctgtccccag gaatgtccag ccgtatgtgg tgtacgaggaggtcaccaac 1620 gtctggatca atgttcatga catcttctat cccttccccc aatcagagggagaggacgag 1680 ctctgctttc tccgcgccaa tgaatgcaag accggcttct gccatttgtacaaagtcacc 1740 gccgttttaa aatcccaggg ctacgattgg agtgagccct tcagccccggggaagatgaa 1800 tttaagtgcc ccattaagga agagattgct ctgaccagcg gtgaatgggaggttttggcg 1860 aggcacggct ccaagatctg ggtcaatgag gagaccaagc tggtgtacttccagggcacc 1920 aaggacacgc cgctggagca ccacctctac gtggtcagct atgaggcggccggcgagatc 1980 gtacgcctca ccacgcccgg cttctcccat agctgctcca tgagccagaacttcgacatg 2040 ttcgtcagcc actacagcag cgtgagcacg ccgccctgcg tgcacgtctacaagctgagc 2100 ggccccgacg acgaccccct gcacaagcag ccccgcttct gggctagcatgatggaggca 2160 gccagctgcc ccccggatta tgttcctcca gagatcttcc atttccacacgcgctcggat 2220 gtgcggctct acggcatgat ctacaagccc cacgccttgc agccagggaagaagcacccc 2280 accgtcctct ttgtatatgg aggcccccag gtgcagctgg tgaataactccttcaaaggc 2340 atcaagtact tgcggctcaa cacactggcc tccctgggct acgccgtggttgtgattgac 2400 ggcaggggct cctgtcagcg agggcttcgg ttcgaagggg ccctgaaaaaccaaatgggc 2460 caggtggaga tcgaggacca ggtggagggc ctgcagttcg tggccgagaagtatggcttc 2520 atcgacctga gccgagttgc catccatggc tggtcctacg ggggcttcctctcgctcatg 2580 gggctaatcc acaagcccca ggtgttcaag gcccaaccgc ttgcttatcctccacggctt 2640 cctggacgaa aacgtgcact ttttccacac aaacttcctc gtctcccaactgatccgagc 2700 agggaaacct taccagctcc agatctaccc caacgagaga cacagtattcgctgccccga 2760 gtcgggcgag cactatgaag tcacgttgct gcactttcta caggaatacctctgagcctg 2820 cccaccggga gccgccacat cacagcacaa gtggctgcag cctccgcggggaaccaggcg 2880 ggagggactg agtggcccgc gggccccagt gaggcacttt gtcccgcccagcgctggcca 2940 gccccgagga gccgctgcct tcaccgcccc gacgcctttt atccttttttaaacgctctt 3000 gggttttatg tccgctgctt cttggttgcc gagacagaga gatggtggtctcgggccagc 3060 ccctcctctc cccgccttct gggaggagga ggtcacacgc tgatgggcactggagaggcc 3120 agaagagact cagaggagcg ggctgccttc cgcctggggc tccctgtgacctctcagtcc 3180 cctggcccgg ccagccaccg tccccagcac ccaagcatgc aattgcctgtcccccccggc 3240 cagcctcccc aacttgatgt ttgtgttttg tttgggggga tatttttcataattatttaa 3300 aagacaggcc gggcgcggtg gctcacgtct gtaatcccag cactttgggaggctgaggcg 3360 ggcggatcac ctgaggttgg gagttcaaga ccagcctggc caacatggggaaaccccgtc 3420 tctactaaaa atacaaaaaa ttagccgggt gtggtggcgc gtgcctataatcccagctac 3480 tcgggaggct gaggcaggag aatcgcttga acccgggagg tggaggttgcggtgagccaa 3540 gatcgcacca ttgcactcca gcctgggcaa caagagcgaa actctgtctcaaaataaata 3600 aaaaataaaa gacagaaagc aaggggtgcc taaatctaga cttggggtccacaccgggca 3660 gcggggttgc aacccagcac ctggtaggct ccatttcttc ccaagcccgactttcaggca 3720 ggcactgaaa cgcaccgaac ttccacgctc tgctggtcag tggcggctgtcccctcccca 3780 gcccagccgc ccagccacat gtgtctgcct gacccgtaca caccaggggttccggggttg 3840 ggagctgaac catccccacc tcagggttat atttccctct ccccttccctccccgccaag 3900 agctctgcca ggggcgggca aaaaaaaaag taaaaagaaa agaaaaaaaaaaaaaagaaa 3960 caaaccacct ctacatatta tggaaagaaa atatttttgt cgattcttattcttttataa 4020 ttatgcgtgg aagaagtaga cacattaaac gattccagtt ggaaacatgtcacctg 4076 33 879 PRT Homo sapiens 33 Met Arg Lys Val Lys Lys Leu ArgLeu Asp Lys Glu Asn Thr Gly Ser 1 5 10 15 Trp Arg Ser Phe Ser Leu AsnSer Glu Gly Ala Glu Arg Met Ala Thr 20 25 30 Thr Gly Thr Pro Thr Ala AspArg Gly Asp Ala Ala Ala Thr Asp Asp 35 40 45 Pro Ala Ala Arg Phe Gln ValGln Lys His Ser Trp Asp Gly Leu Arg 50 55 60 Ser Ile Ile His Gly Ser ArgLys Tyr Ser Gly Leu Ile Val Asn Lys 65 70 75 80 Ala Pro His Asp Phe GlnPhe Val Gln Lys Thr Asp Glu Ser Gly Pro 85 90 95 His Ser His Arg Leu TyrTyr Leu Gly Met Pro Tyr Gly Ser Arg Glu 100 105 110 Asn Ser Leu Leu TyrSer Glu Ile Pro Lys Lys Val Arg Lys Glu Ala 115 120 125 Leu Leu Leu LeuSer Trp Lys Gln Met Leu Asp His Phe Gln Ala Thr 130 135 140 Pro His HisGly Val Tyr Ser Arg Glu Glu Glu Leu Leu Arg Glu Arg 145 150 155 160 LysArg Leu Gly Val Phe Gly Ile Thr Ser Tyr Asp Phe His Ser Glu 165 170 175Ser Gly Leu Phe Leu Phe Gln Ala Ser Asn Ser Leu Phe His Cys Arg 180 185190 Asp Gly Gly Lys Asn Gly Phe Met Val Ser Pro Met Lys Pro Leu Glu 195200 205 Ile Lys Thr Gln Cys Ser Gly Pro Arg Met Asp Pro Lys Ile Cys Pro210 215 220 Ala Asp Pro Ala Phe Phe Ser Phe Ile Asn Asn Ser Asp Leu TrpVal 225 230 235 240 Ala Asn Ile Glu Thr Gly Glu Glu Arg Arg Leu Thr PheCys His Gln 245 250 255 Gly Leu Ser Asn Val Leu Asp Asp Pro Lys Ser AlaGly Val Ala Thr 260 265 270 Phe Val Ile Gln Glu Glu Phe Asp Arg Phe ThrGly Tyr Trp Trp Cys 275 280 285 Pro Thr Ala Ser Trp Glu Gly Ser Glu GlyLeu Lys Thr Leu Arg Ile 290 295 300 Leu Tyr Glu Glu Val Asp Glu Ser GluVal Glu Val Ile His Val Pro 305 310 315 320 Ser Pro Ala Leu Glu Glu ArgLys Thr Asp Ser Tyr Arg Tyr Pro Arg 325 330 335 Thr Gly Ser Lys Asn ProLys Ile Ala Leu Lys Leu Ala Glu Phe Gln 340 345 350 Thr Asp Ser Gln GlyLys Ile Val Ser Thr Gln Glu Lys Glu Leu Val 355 360 365 Gln Pro Phe SerSer Leu Phe Pro Lys Val Glu Tyr Ile Ala Arg Ala 370 375 380 Gly Trp ThrArg Asp Gly Lys Tyr Ala Trp Ala Met Phe Leu Asp Arg 385 390 395 400 ProGln Gln Trp Leu Gln Leu Val Leu Leu Pro Pro Ala Leu Phe Ile 405 410 415Pro Ser Thr Glu Asn Glu Glu Gln Arg Leu Ala Ser Ala Arg Ala Val 420 425430 Pro Arg Asn Val Gln Pro Tyr Val Val Tyr Glu Glu Val Thr Asn Val 435440 445 Trp Ile Asn Val His Asp Ile Phe Tyr Pro Phe Pro Gln Ser Glu Gly450 455 460 Glu Asp Glu Leu Cys Phe Leu Arg Ala Asn Glu Cys Lys Thr GlyPhe 465 470 475 480 Cys His Leu Tyr Lys Val Thr Ala Val Leu Lys Ser GlnGly Tyr Asp 485 490 495 Trp Ser Glu Pro Phe Ser Pro Gly Glu Asp Glu PheLys Cys Pro Ile 500 505 510 Lys Glu Glu Ile Ala Leu Thr Ser Gly Glu TrpGlu Val Leu Ala Arg 515 520 525 His Gly Ser Lys Gly Thr Lys Asp Thr ProLeu Glu His His Leu Tyr 530 535 540 Val Val Ser Tyr Glu Ala Ala Gly GluIle Val Arg Leu Thr Thr Pro 545 550 555 560 Gly Phe Ser His Ser Cys SerMet Ser Gln Asn Phe Asp Met Phe Val 565 570 575 Ser His Tyr Ser Ser ValSer Thr Pro Pro Cys Val His Val Tyr Lys 580 585 590 Leu Ser Gly Pro AspAsp Asp Pro Leu His Lys Gln Pro Arg Phe Trp 595 600 605 Ala Ser Met MetGlu Ala Ala Ser Cys Pro Pro Asp Tyr Val Pro Pro 610 615 620 Glu Ile PheHis Phe His Thr Arg Ser Asp Val Arg Leu Tyr Gly Met 625 630 635 640 IleTyr Lys Pro His Ala Leu Gln Pro Gly Lys Lys His Pro Thr Val 645 650 655Leu Phe Val Tyr Gly Gly Pro Gln Val Gln Leu Val Asn Asn Ser Phe 660 665670 Lys Gly Ile Lys Tyr Leu Arg Leu Asn Thr Leu Ala Ser Leu Gly Tyr 675680 685 Ala Val Val Val Ile Asp Gly Arg Gly Ser Cys Gln Arg Gly Leu Arg690 695 700 Phe Glu Gly Ala Leu Lys Asn Gln Met Gly Gln Val Glu Ile GluAsp 705 710 715 720 Gln Val Glu Gly Leu Gln Phe Val Ala Glu Lys Tyr GlyPhe Ile Asp 725 730 735 Leu Ser Arg Val Ala Ile His Gly Trp Ser Tyr GlyGly Phe Leu Ser 740 745 750 Leu Met Gly Leu Ile His Lys Pro Gln Val PheLys Val Ala Ile Ala 755 760 765 Gly Ala Pro Val Thr Val Trp Met Ala TyrAsp Thr Gly Tyr Thr Glu 770 775 780 Arg Tyr Met Asp Val Pro Glu Asn AsnGln His Gly Tyr Glu Ala Gly 785 790 795 800 Ser Val Ala Leu His Val GluLys Leu Pro Asn Glu Pro Asn Arg Leu 805 810 815 Leu Ile Leu His Gly PheLeu Asp Glu Asn Val His Phe Phe His Thr 820 825 830 Asn Phe Leu Val SerGln Leu Ile Arg Ala Gly Lys Pro Tyr Gln Leu 835 840 845 Gln Ile Tyr ProAsn Glu Arg His Ser Ile Arg Cys Pro Glu Ser Gly 850 855 860 Glu His TyrGlu Val Thr Leu Leu His Phe Leu Gln Glu Tyr Leu 865 870 875 34 4263 DNAHomo sapiens 34 caggccgccg cctgggtcgc tcaacttccg ggtcaaaggt gcctgagccggcgggtcccc 60 tgtgtccgcc gcggctgtcg tcccccgctc ccgccacttc cggggtcgcagtcccgggca 120 tggagccgcg accgtgaggc gccgctggac ccgggacgac ctgcccagtccggccgccgc 180 cccacgtccc ggtctgtgtc ccacgcctgc agctggaatg gaggctctctggacccttta 240 gaaggcaccc ctgccctcct gaggtcagct gagcggttaa tgcggaaggttaagaaactg 300 cgcctggaca aggagaacac cggaagttgg agaagcttct cgctgaattccgagggggct 360 gagaggatgg ccaccaccgg gaccccaacg gccgaccgag gcgacgcagccgccacagat 420 gacccggccg cccgcttcca ggtgcagaag cactcgtggg acgggctccggagcatcatc 480 cacggcagcc gcaagtactc gggcctcatt gtcaacaagg cgccccacgacttccagttt 540 gtgcagaaga cggatgagtc tgggccccac tcccaccgcc tctactacctgggaatgcca 600 tatggcagcc gagagaactc cctcctctac tctgagattc ccaagaaggtccggaaagag 660 gctctgctgc tcctgtcctg gaagcagatg ctggatcatt tccaggccacgccccaccat 720 ggggtctact ctcgggagga ggagctgctg agggagcgga aacgcctgggggtcttcggc 780 atcacctcct acgacttcca cagcgagagt ggcctcttcc tcttccaggccagcaacagc 840 ctcttccact gccgcgacgg cggcaagaac ggcttcatgg tgtcccctatgaaaccgctg 900 gaaatcaaga cccagtgctc agggccccgg atggacccca aaatctgccctgccgaccct 960 gccttcttct ccttcatcaa taacagcgac ctgtgggtgg ccaacatcgagacaggcgag 1020 gagcggcggc tgaccttctg ccaccaaggt ttatccaatg tcctggatgaccccaagtct 1080 gcgggtgtgg ccaccttcgt catacaggaa gagttcgacc gcttcactgggtactggtgg 1140 tgccccacag cctcctggga aggttcagag ggcctcaaga cgctgcgaatcctgtatgag 1200 gaagtcgatg agtccgaggt ggaggtcatt cacgtcccct ctcctgcgctagaagaaagg 1260 aagacggact cgtatcggta ccccaggaca ggcagcaaga atcccaagattgccttgaaa 1320 ctggctgagt tccagactga cagccagggc aagatcgtct cgacccaggagaaggagctg 1380 gtgcagccct tcagctcgct gttcccgaag gtggagtaca tcgccagggccgggtggacc 1440 cgggatggca aatacgcctg ggccatgttc ctggaccggc cccagcagtggctccagctc 1500 gtcctcctcc ccccggccct gttcatcccg agcacagaga atgaggagcagcggctagcc 1560 tctgccagag ctgtccccag gaatgtccag ccgtatgtgg tgtacgaggaggtcaccaac 1620 gtctggatca atgttcatga catcttctat cccttccccc aatcagagggagaggacgag 1680 ctctgctttc tccgcgccaa tgaatgcaag accggcttct gccatttgtacaaagtcacc 1740 gccgttttaa aatcccaggg ctacgattgg agtgagccct tcagccccggggaagatgaa 1800 tttaagtgcc ccattaagga agagattgct ctgaccagcg gtgaatgggaggttttggcg 1860 aggcacggct ccaagggcac caaggacacg ccgctggagc accacctctacgtggtcagc 1920 tatgaggcgg ccggcgagat cgtacgcctc accacgcccg gcttctcccatagctgctcc 1980 atgagccaga acttcgacat gttcgtcagc cactacagca gcgtgagcacgccgccctgc 2040 gtgcacgtct acaagctgag cggccccgac gacgaccccc tgcacaagcagccccgcttc 2100 tgggctagca tgatggaggc agccagctgc cccccggatt atgttcctccagagatcttc 2160 catttccaca cgcgctcgga tgtgcggctc tacggcatga tctacaagccccacgccttg 2220 cagccaggga agaagcaccc caccgtcctc tttgtatatg gaggcccccaggtgcagctg 2280 gtgaataact ccttcaaagg catcaagtac ttgcggctca acacactggcctccctgggc 2340 tacgccgtgg ttgtgattga cggcaggggc tcctgtcagc gagggcttcggttcgaaggg 2400 gccctgaaaa accaaatggg ccaggtggag atcgaggacc aggtggagggcctgcagttc 2460 gtggccgaga agtatggctt catcgacctg agccgagttg ccatccatggctggtcctac 2520 gggggcttcc tctcgctcat ggggctaatc cacaagcccc aggtgttcaaggtggccatc 2580 gcgggtgccc cggtcaccgt ctggatggcc tacgacacag ggtacactgagcgctacatg 2640 gacgtccctg agaacaacca gcacggctat gaggcgggtt ccgtggccctgcacgtggag 2700 aagctgccca atgagcccaa ccgcttgctt atcctccacg gcttcctggacgaaaacgtg 2760 cactttttcc acacaaactt cctcgtctcc caactgatcc gagcagggaaaccttaccag 2820 ctccagatct accccaacga gagacacagt attcgctgcc ccgagtcgggcgagcactat 2880 gaagtcacgt tgctgcactt tctacaggaa tacctctgag cctgcccaccgggagccgcc 2940 acatcacagc acaagtggct gcagcctccg cggggaacca ggcgggagggactgagtggc 3000 ccgcgggccc cagtgaggca ctttgtcccg cccagcgctg gccagccccgaggagccgct 3060 gccttcaccg ccccgacgcc ttttatcctt ttttaaacgc tcttgggttttatgtccgct 3120 gcttcttggt tgccgagaca gagagatggt ggtctcgggc cagcccctcctctccccgcc 3180 ttctgggagg aggaggtcac acgctgatgg gcactggaga ggccagaagagactcagagg 3240 agcgggctgc cttccgcctg gggctccctg tgacctctca gtcccctggcccggccagcc 3300 accgtcccca gcacccaagc atgcaattgc ctgtcccccc cggccagcctccccaacttg 3360 atgtttgtgt tttgtttggg gggatatttt tcataattat ttaaaagacaggccgggcgc 3420 ggtggctcac gtctgtaatc ccagcacttt gggaggctga ggcgggcggatcacctgagg 3480 ttgggagttc aagaccagcc tggccaacat ggggaaaccc cgtctctactaaaaatacaa 3540 aaaattagcc gggtgtggtg gcgcgtgcct ataatcccag ctactcgggaggctgaggca 3600 ggagaatcgc ttgaacccgg gaggtggagg ttgcggtgag ccaagatcgcaccattgcac 3660 tccagcctgg gcaacaagag cgaaactctg tctcaaaata aataaaaaataaaagacaga 3720 aagcaagggg tgcctaaatc tagacttggg gtccacaccg ggcagcggggttgcaaccca 3780 gcacctggta ggctccattt cttcccaagc ccgagcagag ggtcatgcgggccccacagg 3840 agaagcggcc agggcccgcg gggggcacca cctgtggaca gccctcctgtccccaagctt 3900 tcaggcaggc actgaaacgc accgaacttc cacgctctgc tggtcagtggcggctgtccc 3960 ctccccagcc cagccgccca gccacatgtg tctgcctgac ccgtacacaccaggggttcc 4020 ggggttggga gctgaaccat ccccacctca gggttatatt tccctctccccttccctccc 4080 cgccaagagc tctgccaggg gcgggcaaaa aaaaaagtaa aaagaaaagaaaaaaaaaaa 4140 aaagaaacaa accacctcta catattatgg aaagaaaata tttttgtcgattcttattct 4200 tttataatta tgcgtggaag aagtagacac attaaacgat tccagttggaaacatgtcac 4260 ctg 4263 35 879 PRT Homo sapiens 35 Met Arg Lys Val LysLys Leu Arg Leu Asp Lys Glu Asn Thr Gly Ser 1 5 10 15 Trp Arg Ser PheSer Leu Asn Ser Glu Gly Ala Glu Arg Met Ala Thr 20 25 30 Thr Gly Thr ProThr Ala Asp Arg Gly Asp Ala Ala Ala Thr Asp Asp 35 40 45 Pro Ala Ala ArgPhe Gln Val Gln Lys His Ser Trp Asp Gly Leu Arg 50 55 60 Ser Ile Ile HisGly Ser Arg Lys Tyr Ser Gly Leu Ile Val Asn Lys 65 70 75 80 Ala Pro HisAsp Phe Gln Phe Val Gln Lys Thr Asp Glu Ser Gly Pro 85 90 95 His Ser HisArg Leu Tyr Tyr Leu Gly Met Pro Tyr Gly Ser Arg Glu 100 105 110 Asn SerLeu Leu Tyr Ser Glu Ile Pro Lys Lys Val Arg Lys Glu Ala 115 120 125 LeuLeu Leu Leu Ser Trp Lys Gln Met Leu Asp His Phe Gln Ala Thr 130 135 140Pro His His Gly Val Tyr Ser Arg Glu Glu Glu Leu Leu Arg Glu Arg 145 150155 160 Lys Arg Leu Gly Val Phe Gly Ile Thr Ser Tyr Asp Phe His Ser Glu165 170 175 Ser Gly Leu Phe Leu Phe Gln Ala Ser Asn Ser Leu Phe His CysArg 180 185 190 Asp Gly Gly Lys Asn Gly Phe Met Val Ser Pro Met Lys ProLeu Glu 195 200 205 Ile Lys Thr Gln Cys Ser Gly Pro Arg Met Asp Pro LysIle Cys Pro 210 215 220 Ala Asp Pro Ala Phe Phe Ser Phe Ile Asn Asn SerAsp Leu Trp Val 225 230 235 240 Ala Asn Ile Glu Thr Gly Glu Glu Arg ArgLeu Thr Phe Cys His Gln 245 250 255 Gly Leu Ser Asn Val Leu Asp Asp ProLys Ser Ala Gly Val Ala Thr 260 265 270 Phe Val Ile Gln Glu Glu Phe AspArg Phe Thr Gly Tyr Trp Trp Cys 275 280 285 Pro Thr Ala Ser Trp Glu GlySer Glu Gly Leu Lys Thr Leu Arg Ile 290 295 300 Leu Tyr Glu Glu Val AspGlu Ser Glu Val Glu Val Ile His Val Pro 305 310 315 320 Ser Pro Ala LeuGlu Glu Arg Lys Thr Asp Ser Tyr Arg Tyr Pro Arg 325 330 335 Thr Gly SerLys Asn Pro Lys Ile Ala Leu Lys Leu Ala Glu Phe Gln 340 345 350 Thr AspSer Gln Gly Lys Ile Val Ser Thr Gln Glu Lys Glu Leu Val 355 360 365 GlnPro Phe Ser Ser Leu Phe Pro Lys Val Glu Tyr Ile Ala Arg Ala 370 375 380Gly Trp Thr Arg Asp Gly Lys Tyr Ala Trp Ala Met Phe Leu Asp Arg 385 390395 400 Pro Gln Gln Trp Leu Gln Leu Val Leu Leu Pro Pro Ala Leu Phe Ile405 410 415 Pro Ser Thr Glu Asn Glu Glu Gln Arg Leu Ala Ser Ala Arg AlaVal 420 425 430 Pro Arg Asn Val Gln Pro Tyr Val Val Tyr Glu Glu Val ThrAsn Val 435 440 445 Trp Ile Asn Val His Asp Ile Phe Tyr Pro Phe Pro GlnSer Glu Gly 450 455 460 Glu Asp Glu Leu Cys Phe Leu Arg Ala Asn Glu CysLys Thr Gly Phe 465 470 475 480 Cys His Leu Tyr Lys Val Thr Ala Val LeuLys Ser Gln Gly Tyr Asp 485 490 495 Trp Ser Glu Pro Phe Ser Pro Gly GluAsp Glu Phe Lys Cys Pro Ile 500 505 510 Lys Glu Glu Ile Ala Leu Thr SerGly Glu Trp Glu Val Leu Ala Arg 515 520 525 His Gly Ser Lys Gly Thr LysAsp Thr Pro Leu Glu His His Leu Tyr 530 535 540 Val Val Ser Tyr Glu AlaAla Gly Glu Ile Val Arg Leu Thr Thr Pro 545 550 555 560 Gly Phe Ser HisSer Cys Ser Met Ser Gln Asn Phe Asp Met Phe Val 565 570 575 Ser His TyrSer Ser Val Ser Thr Pro Pro Cys Val His Val Tyr Lys 580 585 590 Leu SerGly Pro Asp Asp Asp Pro Leu His Lys Gln Pro Arg Phe Trp 595 600 605 AlaSer Met Met Glu Ala Ala Ser Cys Pro Pro Asp Tyr Val Pro Pro 610 615 620Glu Ile Phe His Phe His Thr Arg Ser Asp Val Arg Leu Tyr Gly Met 625 630635 640 Ile Tyr Lys Pro His Ala Leu Gln Pro Gly Lys Lys His Pro Thr Val645 650 655 Leu Phe Val Tyr Gly Gly Pro Gln Val Gln Leu Val Asn Asn SerPhe 660 665 670 Lys Gly Ile Lys Tyr Leu Arg Leu Asn Thr Leu Ala Ser LeuGly Tyr 675 680 685 Ala Val Val Val Ile Asp Gly Arg Gly Ser Cys Gln ArgGly Leu Arg 690 695 700 Phe Glu Gly Ala Leu Lys Asn Gln Met Gly Gln ValGlu Ile Glu Asp 705 710 715 720 Gln Val Glu Gly Leu Gln Phe Val Ala GluLys Tyr Gly Phe Ile Asp 725 730 735 Leu Ser Arg Val Ala Ile His Gly TrpSer Tyr Gly Gly Phe Leu Ser 740 745 750 Leu Met Gly Leu Ile His Lys ProGln Val Phe Lys Val Ala Ile Ala 755 760 765 Gly Ala Pro Val Thr Val TrpMet Ala Tyr Asp Thr Gly Tyr Thr Glu 770 775 780 Arg Tyr Met Asp Val ProGlu Asn Asn Gln His Gly Tyr Glu Ala Gly 785 790 795 800 Ser Val Ala LeuHis Val Glu Lys Leu Pro Asn Glu Pro Asn Arg Leu 805 810 815 Leu Ile LeuHis Gly Phe Leu Asp Glu Asn Val His Phe Phe His Thr 820 825 830 Asn PheLeu Val Ser Gln Leu Ile Arg Ala Gly Lys Pro Tyr Gln Leu 835 840 845 GlnIle Tyr Pro Asn Glu Arg His Ser Ile Arg Cys Pro Glu Ser Gly 850 855 860Glu His Tyr Glu Val Thr Leu Leu His Phe Leu Gln Glu Tyr Leu 865 870 87536 4180 DNA Homo sapiens 36 caggccgccg cctgggtcgc tcaacttccg ggtcaaaggtgcctgagccg gcgggtcccc 60 tgtgtccgcc gcggctgtcg tcccccgctc ccgccacttccggggtcgca gtcccgggca 120 tggagccgcg accgtgaggc gccgctggac ccgggacgacctgcccagtc cggccgccgc 180 cccacgtccc ggtctgtgtc ccacgcctgc agctggaatggaggctctct ggacccttta 240 gaaggcaccc ctgccctcct gaggtcagct gagcggttaatgcggaaggt taagaaactg 300 cgcctggaca aggagaacac cggaagttgg agaagcttctcgctgaattc cgagggggct 360 gagaggatgg ccaccaccgg gaccccaacg gccgaccgaggcgacgcagc cgccacagat 420 gacccggccg cccgcttcca ggtgcagaag cactcgtgggacgggctccg gagcatcatc 480 cacggcagcc gcaagtactc gggcctcatt gtcaacaaggcgccccacga cttccagttt 540 gtgcagaaga cggatgagtc tgggccccac tcccaccgcctctactacct gggaatgcca 600 tatggcagcc gagagaactc cctcctctac tctgagattcccaagaaggt ccggaaagag 660 gctctgctgc tcctgtcctg gaagcagatg ctggatcatttccaggccac gccccaccat 720 ggggtctact ctcgggagga ggagctgctg agggagcggaaacgcctggg ggtcttcggc 780 atcacctcct acgacttcca cagcgagagt ggcctcttcctcttccaggc cagcaacagc 840 ctcttccact gccgcgacgg cggcaagaac ggcttcatggtgtcccctat gaaaccgctg 900 gaaatcaaga cccagtgctc agggccccgg atggaccccaaaatctgccc tgccgaccct 960 gccttcttct ccttcatcaa taacagcgac ctgtgggtggccaacatcga gacaggcgag 1020 gagcggcggc tgaccttctg ccaccaaggt ttatccaatgtcctggatga ccccaagtct 1080 gcgggtgtgg ccaccttcgt catacaggaa gagttcgaccgcttcactgg gtactggtgg 1140 tgccccacag cctcctggga aggttcagag ggcctcaagacgctgcgaat cctgtatgag 1200 gaagtcgatg agtccgaggt ggaggtcatt cacgtcccctctcctgcgct agaagaaagg 1260 aagacggact cgtatcggta ccccaggaca ggcagcaagaatcccaagat tgccttgaaa 1320 ctggctgagt tccagactga cagccagggc aagatcgtctcgacccagga gaaggagctg 1380 gtgcagccct tcagctcgct gttcccgaag gtggagtacatcgccagggc cgggtggacc 1440 cgggatggca aatacgcctg ggccatgttc ctggaccggccccagcagtg gctccagctc 1500 gtcctcctcc ccccggccct gttcatcccg agcacagagaatgaggagca gcggctagcc 1560 tctgccagag ctgtccccag gaatgtccag ccgtatgtggtgtacgagga ggtcaccaac 1620 gtctggatca atgttcatga catcttctat cccttcccccaatcagaggg agaggacgag 1680 ctctgctttc tccgcgccaa tgaatgcaag accggcttctgccatttgta caaagtcacc 1740 gccgttttaa aatcccaggg ctacgattgg agtgagcccttcagccccgg ggaagatgaa 1800 tttaagtgcc ccattaagga agagattgct ctgaccagcggtgaatggga ggttttggcg 1860 aggcacggct ccaagggcac caaggacacg ccgctggagcaccacctcta cgtggtcagc 1920 tatgaggcgg ccggcgagat cgtacgcctc accacgcccggcttctccca tagctgctcc 1980 atgagccaga acttcgacat gttcgtcagc cactacagcagcgtgagcac gccgccctgc 2040 gtgcacgtct acaagctgag cggccccgac gacgaccccctgcacaagca gccccgcttc 2100 tgggctagca tgatggaggc agccagctgc cccccggattatgttcctcc agagatcttc 2160 catttccaca cgcgctcgga tgtgcggctc tacggcatgatctacaagcc ccacgccttg 2220 cagccaggga agaagcaccc caccgtcctc tttgtatatggaggccccca ggtgcagctg 2280 gtgaataact ccttcaaagg catcaagtac ttgcggctcaacacactggc ctccctgggc 2340 tacgccgtgg ttgtgattga cggcaggggc tcctgtcagcgagggcttcg gttcgaaggg 2400 gccctgaaaa accaaatggg ccaggtggag atcgaggaccaggtggaggg cctgcagttc 2460 gtggccgaga agtatggctt catcgacctg agccgagttgccatccatgg ctggtcctac 2520 gggggcttcc tctcgctcat ggggctaatc cacaagccccaggtgttcaa ggtggccatc 2580 gcgggtgccc cggtcaccgt ctggatggcc tacgacacagggtacactga gcgctacatg 2640 gacgtccctg agaacaacca gcacggctat gaggcgggttccgtggccct gcacgtggag 2700 aagctgccca atgagcccaa ccgcttgctt atcctccacggcttcctgga cgaaaacgtg 2760 cactttttcc acacaaactt cctcgtctcc caactgatccgagcagggaa accttaccag 2820 ctccagatct accccaacga gagacacagt attcgctgccccgagtcggg cgagcactat 2880 gaagtcacgt tgctgcactt tctacaggaa tacctctgagcctgcccacc gggagccgcc 2940 acatcacagc acaagtggct gcagcctccg cggggaaccaggcgggaggg actgagtggc 3000 ccgcgggccc cagtgaggca ctttgtcccg cccagcgctggccagccccg aggagccgct 3060 gccttcaccg ccccgacgcc ttttatcctt ttttaaacgctcttgggttt tatgtccgct 3120 gcttcttggt tgccgagaca gagagatggt ggtctcgggccagcccctcc tctccccgcc 3180 ttctgggagg aggaggtcac acgctgatgg gcactggagaggccagaaga gactcagagg 3240 agcgggctgc cttccgcctg gggctccctg tgacctctcagtcccctggc ccggccagcc 3300 accgtcccca gcacccaagc atgcaattgc ctgtcccccccggccagcct ccccaacttg 3360 atgtttgtgt tttgtttggg gggatatttt tcataattatttaaaagaca ggccgggcgc 3420 ggtggctcac gtctgtaatc ccagcacttt gggaggctgaggcgggcgga tcacctgagg 3480 ttgggagttc aagaccagcc tggccaacat ggggaaaccccgtctctact aaaaatacaa 3540 aaaattagcc gggtgtggtg gcgcgtgcct ataatcccagctactcggga ggctgaggca 3600 ggagaatcgc ttgaacccgg gaggtggagg ttgcggtgagccaagatcgc accattgcac 3660 tccagcctgg gcaacaagag cgaaactctg tctcaaaataaataaaaaat aaaagacaga 3720 aagcaagggg tgcctaaatc tagacttggg gtccacaccgggcagcgggg ttgcaaccca 3780 gcacctggta ggctccattt cttcccaagc ccgactttcaggcaggcact gaaacgcacc 3840 gaacttccac gctctgctgg tcagtggcgg ctgtcccctccccagcccag ccgcccagcc 3900 acatgtgtct gcctgacccg tacacaccag gggttccggggttgggagct gaaccatccc 3960 cacctcaggg ttatatttcc ctctcccctt ccctccccgccaagagctct gccaggggcg 4020 ggcaaaaaaa aaagtaaaaa gaaaagaaaa aaaaaaaaaagaaacaaacc acctctacat 4080 attatggaaa gaaaatattt ttgtcgattc ttattcttttataattatgc gtggaagaag 4140 tagacacatt aaacgattcc agttggaaac atgtcacctg4180 37 819 PRT Homo sapiens 37 Met Arg Lys Val Lys Lys Leu Arg Leu AspLys Glu Asn Thr Gly Ser 1 5 10 15 Trp Arg Ser Phe Ser Leu Asn Ser GluGly Ala Glu Arg Met Ala Thr 20 25 30 Thr Gly Thr Pro Thr Ala Asp Arg GlyAsp Ala Ala Ala Thr Asp Asp 35 40 45 Pro Ala Ala Arg Phe Gln Val Gln LysHis Ser Trp Asp Gly Leu Arg 50 55 60 Ser Ile Ile His Gly Ser Arg Lys TyrSer Gly Leu Ile Val Asn Lys 65 70 75 80 Ala Pro His Asp Phe Gln Phe ValGln Lys Thr Asp Glu Ser Gly Pro 85 90 95 His Ser His Arg Leu Tyr Tyr LeuGly Met Pro Tyr Gly Ser Arg Glu 100 105 110 Asn Ser Leu Leu Tyr Ser GluIle Pro Lys Lys Val Arg Lys Glu Ala 115 120 125 Leu Leu Leu Leu Ser TrpLys Gln Met Leu Asp His Phe Gln Ala Thr 130 135 140 Pro His His Gly ValTyr Ser Arg Glu Glu Glu Leu Leu Arg Glu Arg 145 150 155 160 Lys Arg LeuGly Val Phe Gly Ile Thr Ser Tyr Asp Phe His Ser Glu 165 170 175 Ser GlyLeu Phe Leu Phe Gln Ala Ser Asn Ser Leu Phe His Cys Arg 180 185 190 AspGly Gly Lys Asn Gly Phe Met Val Ser Pro Met Lys Pro Leu Glu 195 200 205Ile Lys Thr Gln Cys Ser Gly Pro Arg Met Asp Pro Lys Ile Cys Pro 210 215220 Ala Asp Pro Ala Phe Phe Ser Phe Ile Asn Asn Ser Asp Leu Trp Val 225230 235 240 Ala Asn Ile Glu Thr Gly Glu Glu Arg Arg Leu Thr Phe Cys HisGln 245 250 255 Gly Leu Ser Asn Val Leu Asp Asp Pro Lys Ser Ala Gly ValAla Thr 260 265 270 Phe Val Ile Gln Glu Glu Phe Asp Arg Phe Thr Gly TyrTrp Trp Cys 275 280 285 Pro Thr Ala Ser Trp Glu Gly Ser Glu Gly Leu LysThr Leu Arg Ile 290 295 300 Leu Tyr Glu Glu Val Asp Glu Ser Glu Val GluVal Ile His Val Pro 305 310 315 320 Ser Pro Ala Leu Glu Glu Arg Lys ThrAsp Ser Tyr Arg Tyr Pro Arg 325 330 335 Thr Gly Ser Lys Asn Pro Lys IleAla Leu Lys Leu Ala Glu Phe Gln 340 345 350 Thr Asp Ser Gln Gly Lys IleVal Ser Thr Gln Glu Lys Glu Leu Val 355 360 365 Gln Pro Phe Ser Ser LeuPhe Pro Lys Val Glu Tyr Ile Ala Arg Ala 370 375 380 Gly Trp Thr Arg AspGly Lys Tyr Ala Trp Ala Met Phe Leu Asp Arg 385 390 395 400 Pro Gln GlnTrp Leu Gln Leu Val Leu Leu Pro Pro Ala Leu Phe Ile 405 410 415 Pro SerThr Glu Asn Glu Glu Gln Arg Leu Ala Ser Ala Arg Ala Val 420 425 430 ProArg Asn Val Gln Pro Tyr Val Val Tyr Glu Glu Val Thr Asn Val 435 440 445Trp Ile Asn Val His Asp Ile Phe Tyr Pro Phe Pro Gln Ser Glu Gly 450 455460 Glu Asp Glu Leu Cys Phe Leu Arg Ala Asn Glu Cys Lys Thr Gly Phe 465470 475 480 Cys His Leu Tyr Lys Val Thr Ala Val Leu Lys Ser Gln Gly TyrAsp 485 490 495 Trp Ser Glu Pro Phe Ser Pro Gly Glu Asp Glu Phe Lys CysPro Ile 500 505 510 Lys Glu Glu Ile Ala Leu Thr Ser Gly Glu Trp Glu ValLeu Ala Arg 515 520 525 His Gly Ser Lys Gly Thr Lys Asp Thr Pro Leu GluHis His Leu Tyr 530 535 540 Val Val Ser Tyr Glu Ala Ala Gly Glu Ile ValArg Leu Thr Thr Pro 545 550 555 560 Gly Phe Ser His Ser Cys Ser Met SerGln Asn Phe Asp Met Phe Val 565 570 575 Ser His Tyr Ser Ser Val Ser ThrPro Pro Cys Val His Val Tyr Lys 580 585 590 Leu Ser Gly Pro Asp Asp AspPro Leu His Lys Gln Pro Arg Phe Trp 595 600 605 Ala Ser Met Met Glu AlaAla Ser Cys Pro Pro Asp Tyr Val Pro Pro 610 615 620 Glu Ile Phe His PheHis Thr Arg Ser Asp Val Arg Leu Tyr Gly Met 625 630 635 640 Ile Tyr LysPro His Ala Leu Gln Pro Gly Lys Lys His Pro Thr Val 645 650 655 Leu PheVal Tyr Gly Gly Pro Gln Val Gln Leu Val Asn Asn Ser Phe 660 665 670 LysGly Ile Lys Tyr Leu Arg Leu Asn Thr Leu Ala Ser Leu Gly Tyr 675 680 685Ala Val Val Val Ile Asp Gly Arg Gly Ser Cys Gln Arg Gly Leu Arg 690 695700 Phe Glu Gly Ala Leu Lys Asn Gln Met Gly Gln Val Glu Ile Glu Asp 705710 715 720 Gln Val Glu Gly Leu Gln Phe Val Ala Glu Lys Tyr Gly Phe IleAsp 725 730 735 Leu Ser Arg Val Ala Ile His Gly Trp Ser Tyr Gly Gly PheLeu Ser 740 745 750 Leu Met Gly Leu Ile His Lys Pro Gln Val Phe Lys AlaGln Pro Leu 755 760 765 Ala Tyr Pro Pro Arg Leu Pro Gly Arg Lys Arg AlaLeu Phe Pro His 770 775 780 Lys Leu Pro Arg Leu Pro Thr Asp Pro Ser ArgGlu Thr Leu Pro Ala 785 790 795 800 Pro Asp Leu Pro Gln Arg Glu Thr GlnTyr Ser Leu Pro Arg Val Gly 805 810 815 Arg Ala Leu 38 4120 DNA Homosapiens 38 caggccgccg cctgggtcgc tcaacttccg ggtcaaaggt gcctgagccggcgggtcccc 60 tgtgtccgcc gcggctgtcg tcccccgctc ccgccacttc cggggtcgcagtcccgggca 120 tggagccgcg accgtgaggc gccgctggac ccgggacgac ctgcccagtccggccgccgc 180 cccacgtccc ggtctgtgtc ccacgcctgc agctggaatg gaggctctctggacccttta 240 gaaggcaccc ctgccctcct gaggtcagct gagcggttaa tgcggaaggttaagaaactg 300 cgcctggaca aggagaacac cggaagttgg agaagcttct cgctgaattccgagggggct 360 gagaggatgg ccaccaccgg gaccccaacg gccgaccgag gcgacgcagccgccacagat 420 gacccggccg cccgcttcca ggtgcagaag cactcgtggg acgggctccggagcatcatc 480 cacggcagcc gcaagtactc gggcctcatt gtcaacaagg cgccccacgacttccagttt 540 gtgcagaaga cggatgagtc tgggccccac tcccaccgcc tctactacctgggaatgcca 600 tatggcagcc gagagaactc cctcctctac tctgagattc ccaagaaggtccggaaagag 660 gctctgctgc tcctgtcctg gaagcagatg ctggatcatt tccaggccacgccccaccat 720 ggggtctact ctcgggagga ggagctgctg agggagcgga aacgcctgggggtcttcggc 780 atcacctcct acgacttcca cagcgagagt ggcctcttcc tcttccaggccagcaacagc 840 ctcttccact gccgcgacgg cggcaagaac ggcttcatgg tgtcccctatgaaaccgctg 900 gaaatcaaga cccagtgctc agggccccgg atggacccca aaatctgccctgccgaccct 960 gccttcttct ccttcatcaa taacagcgac ctgtgggtgg ccaacatcgagacaggcgag 1020 gagcggcggc tgaccttctg ccaccaaggt ttatccaatg tcctggatgaccccaagtct 1080 gcgggtgtgg ccaccttcgt catacaggaa gagttcgacc gcttcactgggtactggtgg 1140 tgccccacag cctcctggga aggttcagag ggcctcaaga cgctgcgaatcctgtatgag 1200 gaagtcgatg agtccgaggt ggaggtcatt cacgtcccct ctcctgcgctagaagaaagg 1260 aagacggact cgtatcggta ccccaggaca ggcagcaaga atcccaagattgccttgaaa 1320 ctggctgagt tccagactga cagccagggc aagatcgtct cgacccaggagaaggagctg 1380 gtgcagccct tcagctcgct gttcccgaag gtggagtaca tcgccagggccgggtggacc 1440 cgggatggca aatacgcctg ggccatgttc ctggaccggc cccagcagtggctccagctc 1500 gtcctcctcc ccccggccct gttcatcccg agcacagaga atgaggagcagcggctagcc 1560 tctgccagag ctgtccccag gaatgtccag ccgtatgtgg tgtacgaggaggtcaccaac 1620 gtctggatca atgttcatga catcttctat cccttccccc aatcagagggagaggacgag 1680 ctctgctttc tccgcgccaa tgaatgcaag accggcttct gccatttgtacaaagtcacc 1740 gccgttttaa aatcccaggg ctacgattgg agtgagccct tcagccccggggaagatgaa 1800 tttaagtgcc ccattaagga agagattgct ctgaccagcg gtgaatgggaggttttggcg 1860 aggcacggct ccaagggcac caaggacacg ccgctggagc accacctctacgtggtcagc 1920 tatgaggcgg ccggcgagat cgtacgcctc accacgcccg gcttctcccatagctgctcc 1980 atgagccaga acttcgacat gttcgtcagc cactacagca gcgtgagcacgccgccctgc 2040 gtgcacgtct acaagctgag cggccccgac gacgaccccc tgcacaagcagccccgcttc 2100 tgggctagca tgatggaggc agccagctgc cccccggatt atgttcctccagagatcttc 2160 catttccaca cgcgctcgga tgtgcggctc tacggcatga tctacaagccccacgccttg 2220 cagccaggga agaagcaccc caccgtcctc tttgtatatg gaggcccccaggtgcagctg 2280 gtgaataact ccttcaaagg catcaagtac ttgcggctca acacactggcctccctgggc 2340 tacgccgtgg ttgtgattga cggcaggggc tcctgtcagc gagggcttcggttcgaaggg 2400 gccctgaaaa accaaatggg ccaggtggag atcgaggacc aggtggagggcctgcagttc 2460 gtggccgaga agtatggctt catcgacctg agccgagttg ccatccatggctggtcctac 2520 gggggcttcc tctcgctcat ggggctaatc cacaagcccc aggtgttcaaggcccaaccg 2580 cttgcttatc ctccacggct tcctggacga aaacgtgcac tttttccacacaaacttcct 2640 cgtctcccaa ctgatccgag cagggaaacc ttaccagctc cagatctaccccaacgagag 2700 acacagtatt cgctgccccg agtcgggcga gcactatgaa gtcacgttgctgcactttct 2760 acaggaatac ctctgagcct gcccaccggg agccgccaca tcacagcacaagtggctgca 2820 gcctccgcgg ggaaccaggc gggagggact gagtggcccg cgggccccagtgaggcactt 2880 tgtcccgccc agcgctggcc agccccgagg agccgctgcc ttcaccgccccgacgccttt 2940 tatccttttt taaacgctct tgggttttat gtccgctgct tcttggttgccgagacagag 3000 agatggtggt ctcgggccag cccctcctct ccccgccttc tgggaggaggaggtcacacg 3060 ctgatgggca ctggagaggc cagaagagac tcagaggagc gggctgccttccgcctgggg 3120 ctccctgtga cctctcagtc ccctggcccg gccagccacc gtccccagcacccaagcatg 3180 caattgcctg tcccccccgg ccagcctccc caacttgatg tttgtgttttgtttgggggg 3240 atatttttca taattattta aaagacaggc cgggcgcggt ggctcacgtctgtaatccca 3300 gcactttggg aggctgaggc gggcggatca cctgaggttg ggagttcaagaccagcctgg 3360 ccaacatggg gaaaccccgt ctctactaaa aatacaaaaa attagccgggtgtggtggcg 3420 cgtgcctata atcccagcta ctcgggaggc tgaggcagga gaatcgcttgaacccgggag 3480 gtggaggttg cggtgagcca agatcgcacc attgcactcc agcctgggcaacaagagcga 3540 aactctgtct caaaataaat aaaaaataaa agacagaaag caaggggtgcctaaatctag 3600 acttggggtc cacaccgggc agcggggttg caacccagca cctggtaggctccatttctt 3660 cccaagcccg agcagagggt catgcgggcc ccacaggaga agcggccagggcccgcgggg 3720 ggcaccacct gtggacagcc ctcctgtccc caagctttca ggcaggcactgaaacgcacc 3780 gaacttccac gctctgctgg tcagtggcgg ctgtcccctc cccagcccagccgcccagcc 3840 acatgtgtct gcctgacccg tacacaccag gggttccggg gttgggagctgaaccatccc 3900 cacctcaggg ttatatttcc ctctcccctt ccctccccgc caagagctctgccaggggcg 3960 ggcaaaaaaa aaagtaaaaa gaaaagaaaa aaaaaaaaaa gaaacaaaccacctctacat 4020 attatggaaa gaaaatattt ttgtcgattc ttattctttt ataattatgcgtggaagaag 4080 tagacacatt aaacgattcc agttggaaac atgtcacctg 4120 39 819PRT Homo sapiens 39 Met Arg Lys Val Lys Lys Leu Arg Leu Asp Lys Glu AsnThr Gly Ser 1 5 10 15 Trp Arg Ser Phe Ser Leu Asn Ser Glu Gly Ala GluArg Met Ala Thr 20 25 30 Thr Gly Thr Pro Thr Ala Asp Arg Gly Asp Ala AlaAla Thr Asp Asp 35 40 45 Pro Ala Ala Arg Phe Gln Val Gln Lys His Ser TrpAsp Gly Leu Arg 50 55 60 Ser Ile Ile His Gly Ser Arg Lys Tyr Ser Gly LeuIle Val Asn Lys 65 70 75 80 Ala Pro His Asp Phe Gln Phe Val Gln Lys ThrAsp Glu Ser Gly Pro 85 90 95 His Ser His Arg Leu Tyr Tyr Leu Gly Met ProTyr Gly Ser Arg Glu 100 105 110 Asn Ser Leu Leu Tyr Ser Glu Ile Pro LysLys Val Arg Lys Glu Ala 115 120 125 Leu Leu Leu Leu Ser Trp Lys Gln MetLeu Asp His Phe Gln Ala Thr 130 135 140 Pro His His Gly Val Tyr Ser ArgGlu Glu Glu Leu Leu Arg Glu Arg 145 150 155 160 Lys Arg Leu Gly Val PheGly Ile Thr Ser Tyr Asp Phe His Ser Glu 165 170 175 Ser Gly Leu Phe LeuPhe Gln Ala Ser Asn Ser Leu Phe His Cys Arg 180 185 190 Asp Gly Gly LysAsn Gly Phe Met Val Ser Pro Met Lys Pro Leu Glu 195 200 205 Ile Lys ThrGln Cys Ser Gly Pro Arg Met Asp Pro Lys Ile Cys Pro 210 215 220 Ala AspPro Ala Phe Phe Ser Phe Ile Asn Asn Ser Asp Leu Trp Val 225 230 235 240Ala Asn Ile Glu Thr Gly Glu Glu Arg Arg Leu Thr Phe Cys His Gln 245 250255 Gly Leu Ser Asn Val Leu Asp Asp Pro Lys Ser Ala Gly Val Ala Thr 260265 270 Phe Val Ile Gln Glu Glu Phe Asp Arg Phe Thr Gly Tyr Trp Trp Cys275 280 285 Pro Thr Ala Ser Trp Glu Gly Ser Glu Gly Leu Lys Thr Leu ArgIle 290 295 300 Leu Tyr Glu Glu Val Asp Glu Ser Glu Val Glu Val Ile HisVal Pro 305 310 315 320 Ser Pro Ala Leu Glu Glu Arg Lys Thr Asp Ser TyrArg Tyr Pro Arg 325 330 335 Thr Gly Ser Lys Asn Pro Lys Ile Ala Leu LysLeu Ala Glu Phe Gln 340 345 350 Thr Asp Ser Gln Gly Lys Ile Val Ser ThrGln Glu Lys Glu Leu Val 355 360 365 Gln Pro Phe Ser Ser Leu Phe Pro LysVal Glu Tyr Ile Ala Arg Ala 370 375 380 Gly Trp Thr Arg Asp Gly Lys TyrAla Trp Ala Met Phe Leu Asp Arg 385 390 395 400 Pro Gln Gln Trp Leu GlnLeu Val Leu Leu Pro Pro Ala Leu Phe Ile 405 410 415 Pro Ser Thr Glu AsnGlu Glu Gln Arg Leu Ala Ser Ala Arg Ala Val 420 425 430 Pro Arg Asn ValGln Pro Tyr Val Val Tyr Glu Glu Val Thr Asn Val 435 440 445 Trp Ile AsnVal His Asp Ile Phe Tyr Pro Phe Pro Gln Ser Glu Gly 450 455 460 Glu AspGlu Leu Cys Phe Leu Arg Ala Asn Glu Cys Lys Thr Gly Phe 465 470 475 480Cys His Leu Tyr Lys Val Thr Ala Val Leu Lys Ser Gln Gly Tyr Asp 485 490495 Trp Ser Glu Pro Phe Ser Pro Gly Glu Asp Glu Phe Lys Cys Pro Ile 500505 510 Lys Glu Glu Ile Ala Leu Thr Ser Gly Glu Trp Glu Val Leu Ala Arg515 520 525 His Gly Ser Lys Gly Thr Lys Asp Thr Pro Leu Glu His His LeuTyr 530 535 540 Val Val Ser Tyr Glu Ala Ala Gly Glu Ile Val Arg Leu ThrThr Pro 545 550 555 560 Gly Phe Ser His Ser Cys Ser Met Ser Gln Asn PheAsp Met Phe Val 565 570 575 Ser His Tyr Ser Ser Val Ser Thr Pro Pro CysVal His Val Tyr Lys 580 585 590 Leu Ser Gly Pro Asp Asp Asp Pro Leu HisLys Gln Pro Arg Phe Trp 595 600 605 Ala Ser Met Met Glu Ala Ala Ser CysPro Pro Asp Tyr Val Pro Pro 610 615 620 Glu Ile Phe His Phe His Thr ArgSer Asp Val Arg Leu Tyr Gly Met 625 630 635 640 Ile Tyr Lys Pro His AlaLeu Gln Pro Gly Lys Lys His Pro Thr Val 645 650 655 Leu Phe Val Tyr GlyGly Pro Gln Val Gln Leu Val Asn Asn Ser Phe 660 665 670 Lys Gly Ile LysTyr Leu Arg Leu Asn Thr Leu Ala Ser Leu Gly Tyr 675 680 685 Ala Val ValVal Ile Asp Gly Arg Gly Ser Cys Gln Arg Gly Leu Arg 690 695 700 Phe GluGly Ala Leu Lys Asn Gln Met Gly Gln Val Glu Ile Glu Asp 705 710 715 720Gln Val Glu Gly Leu Gln Phe Val Ala Glu Lys Tyr Gly Phe Ile Asp 725 730735 Leu Ser Arg Val Ala Ile His Gly Trp Ser Tyr Gly Gly Phe Leu Ser 740745 750 Leu Met Gly Leu Ile His Lys Pro Gln Val Phe Lys Ala Gln Pro Leu755 760 765 Ala Tyr Pro Pro Arg Leu Pro Gly Arg Lys Arg Ala Leu Phe ProHis 770 775 780 Lys Leu Pro Arg Leu Pro Thr Asp Pro Ser Arg Glu Thr LeuPro Ala 785 790 795 800 Pro Asp Leu Pro Gln Arg Glu Thr Gln Tyr Ser LeuPro Arg Val Gly 805 810 815 Arg Ala Leu 40 4037 DNA Homo sapiens 40caggccgccg cctgggtcgc tcaacttccg ggtcaaaggt gcctgagccg gcgggtcccc 60tgtgtccgcc gcggctgtcg tcccccgctc ccgccacttc cggggtcgca gtcccgggca 120tggagccgcg accgtgaggc gccgctggac ccgggacgac ctgcccagtc cggccgccgc 180cccacgtccc ggtctgtgtc ccacgcctgc agctggaatg gaggctctct ggacccttta 240gaaggcaccc ctgccctcct gaggtcagct gagcggttaa tgcggaaggt taagaaactg 300cgcctggaca aggagaacac cggaagttgg agaagcttct cgctgaattc cgagggggct 360gagaggatgg ccaccaccgg gaccccaacg gccgaccgag gcgacgcagc cgccacagat 420gacccggccg cccgcttcca ggtgcagaag cactcgtggg acgggctccg gagcatcatc 480cacggcagcc gcaagtactc gggcctcatt gtcaacaagg cgccccacga cttccagttt 540gtgcagaaga cggatgagtc tgggccccac tcccaccgcc tctactacct gggaatgcca 600tatggcagcc gagagaactc cctcctctac tctgagattc ccaagaaggt ccggaaagag 660gctctgctgc tcctgtcctg gaagcagatg ctggatcatt tccaggccac gccccaccat 720ggggtctact ctcgggagga ggagctgctg agggagcgga aacgcctggg ggtcttcggc 780atcacctcct acgacttcca cagcgagagt ggcctcttcc tcttccaggc cagcaacagc 840ctcttccact gccgcgacgg cggcaagaac ggcttcatgg tgtcccctat gaaaccgctg 900gaaatcaaga cccagtgctc agggccccgg atggacccca aaatctgccc tgccgaccct 960gccttcttct ccttcatcaa taacagcgac ctgtgggtgg ccaacatcga gacaggcgag 1020gagcggcggc tgaccttctg ccaccaaggt ttatccaatg tcctggatga ccccaagtct 1080gcgggtgtgg ccaccttcgt catacaggaa gagttcgacc gcttcactgg gtactggtgg 1140tgccccacag cctcctggga aggttcagag ggcctcaaga cgctgcgaat cctgtatgag 1200gaagtcgatg agtccgaggt ggaggtcatt cacgtcccct ctcctgcgct agaagaaagg 1260aagacggact cgtatcggta ccccaggaca ggcagcaaga atcccaagat tgccttgaaa 1320ctggctgagt tccagactga cagccagggc aagatcgtct cgacccagga gaaggagctg 1380gtgcagccct tcagctcgct gttcccgaag gtggagtaca tcgccagggc cgggtggacc 1440cgggatggca aatacgcctg ggccatgttc ctggaccggc cccagcagtg gctccagctc 1500gtcctcctcc ccccggccct gttcatcccg agcacagaga atgaggagca gcggctagcc 1560tctgccagag ctgtccccag gaatgtccag ccgtatgtgg tgtacgagga ggtcaccaac 1620gtctggatca atgttcatga catcttctat cccttccccc aatcagaggg agaggacgag 1680ctctgctttc tccgcgccaa tgaatgcaag accggcttct gccatttgta caaagtcacc 1740gccgttttaa aatcccaggg ctacgattgg agtgagccct tcagccccgg ggaagatgaa 1800tttaagtgcc ccattaagga agagattgct ctgaccagcg gtgaatggga ggttttggcg 1860aggcacggct ccaagggcac caaggacacg ccgctggagc accacctcta cgtggtcagc 1920tatgaggcgg ccggcgagat cgtacgcctc accacgcccg gcttctccca tagctgctcc 1980atgagccaga acttcgacat gttcgtcagc cactacagca gcgtgagcac gccgccctgc 2040gtgcacgtct acaagctgag cggccccgac gacgaccccc tgcacaagca gccccgcttc 2100tgggctagca tgatggaggc agccagctgc cccccggatt atgttcctcc agagatcttc 2160catttccaca cgcgctcgga tgtgcggctc tacggcatga tctacaagcc ccacgccttg 2220cagccaggga agaagcaccc caccgtcctc tttgtatatg gaggccccca ggtgcagctg 2280gtgaataact ccttcaaagg catcaagtac ttgcggctca acacactggc ctccctgggc 2340tacgccgtgg ttgtgattga cggcaggggc tcctgtcagc gagggcttcg gttcgaaggg 2400gccctgaaaa accaaatggg ccaggtggag atcgaggacc aggtggaggg cctgcagttc 2460gtggccgaga agtatggctt catcgacctg agccgagttg ccatccatgg ctggtcctac 2520gggggcttcc tctcgctcat ggggctaatc cacaagcccc aggtgttcaa ggcccaaccg 2580cttgcttatc ctccacggct tcctggacga aaacgtgcac tttttccaca caaacttcct 2640cgtctcccaa ctgatccgag cagggaaacc ttaccagctc cagatctacc ccaacgagag 2700acacagtatt cgctgccccg agtcgggcga gcactatgaa gtcacgttgc tgcactttct 2760acaggaatac ctctgagcct gcccaccggg agccgccaca tcacagcaca agtggctgca 2820gcctccgcgg ggaaccaggc gggagggact gagtggcccg cgggccccag tgaggcactt 2880tgtcccgccc agcgctggcc agccccgagg agccgctgcc ttcaccgccc cgacgccttt 2940tatccttttt taaacgctct tgggttttat gtccgctgct tcttggttgc cgagacagag 3000agatggtggt ctcgggccag cccctcctct ccccgccttc tgggaggagg aggtcacacg 3060ctgatgggca ctggagaggc cagaagagac tcagaggagc gggctgcctt ccgcctgggg 3120ctccctgtga cctctcagtc ccctggcccg gccagccacc gtccccagca cccaagcatg 3180caattgcctg tcccccccgg ccagcctccc caacttgatg tttgtgtttt gtttgggggg 3240atatttttca taattattta aaagacaggc cgggcgcggt ggctcacgtc tgtaatccca 3300gcactttggg aggctgaggc gggcggatca cctgaggttg ggagttcaag accagcctgg 3360ccaacatggg gaaaccccgt ctctactaaa aatacaaaaa attagccggg tgtggtggcg 3420cgtgcctata atcccagcta ctcgggaggc tgaggcagga gaatcgcttg aacccgggag 3480gtggaggttg cggtgagcca agatcgcacc attgcactcc agcctgggca acaagagcga 3540aactctgtct caaaataaat aaaaaataaa agacagaaag caaggggtgc ctaaatctag 3600acttggggtc cacaccgggc agcggggttg caacccagca cctggtaggc tccatttctt 3660cccaagcccg actttcaggc aggcactgaa acgcaccgaa cttccacgct ctgctggtca 3720gtggcggctg tcccctcccc agcccagccg cccagccaca tgtgtctgcc tgacccgtac 3780acaccagggg ttccggggtt gggagctgaa ccatccccac ctcagggtta tatttccctc 3840tccccttccc tccccgccaa gagctctgcc aggggcgggc aaaaaaaaaa gtaaaaagaa 3900aagaaaaaaa aaaaaaagaa acaaaccacc tctacatatt atggaaagaa aatatttttg 3960tcgattctta ttcttttata attatgcgtg gaagaagtag acacattaaa cgattccagt 4020tggaaacatg tcacctg 4037 41 706 PRT Homo sapiens 41 Asp Thr Asp Val ValTyr Lys Ser Glu Asn Gly His Val Ile Lys Leu 1 5 10 15 Asn Ile Glu ThrAsn Ala Thr Thr Leu Leu Leu Glu Asn Thr Thr Phe 20 25 30 Val Thr Phe LysAla Ser Arg His Ser Val Ser Pro Asp Leu Lys Tyr 35 40 45 Val Leu Leu AlaTyr Asp Val Lys Gln Ile Phe His Tyr Ser Tyr Thr 50 55 60 Ala Ser Tyr ValIle Tyr Asn Ile His Thr Arg Glu Val Trp Glu Leu 65 70 75 80 Asn Pro ProGlu Val Glu Asp Ser Val Leu Gln Tyr Ala Ala Trp Gly 85 90 95 Val Gln GlyGln Gln Leu Ile Tyr Ile Phe Glu Asn Asn Ile Tyr Tyr 100 105 110 Gln ProAsp Ile Lys Ser Ser Ser Leu Arg Leu Thr Ser Ser Gly Lys 115 120 125 GluGlu Ile Ile Phe Asn Gly Ile Ala Asp Trp Leu Tyr Glu Glu Glu 130 135 140Leu Leu His Ser His Ile Ala His Trp Trp Ser Pro Asp Gly Glu Arg 145 150155 160 Leu Ala Phe Leu Met Ile Asn Asp Ser Leu Val Pro Thr Met Val Ile165 170 175 Pro Arg Phe Thr Gly Ala Leu Tyr Pro Lys Gly Lys Gln Tyr ProTyr 180 185 190 Pro Lys Ala Gly Gln Val Asn Pro Thr Ile Lys Leu Tyr ValVal Asn 195 200 205 Leu Tyr Gly Pro Thr His Thr Leu Glu Leu Met Pro ProAsp Ser Phe 210 215 220 Lys Ser Arg Glu Tyr Tyr Ile Thr Met Val Lys TrpVal Ser Asn Thr 225 230 235 240 Lys Thr Val Val Arg Trp Leu Asn Arg ProGln Asn Ile Ser Ile Leu 245 250 255 Thr Val Cys Glu Thr Thr Thr Gly AlaCys Ser Lys Lys Tyr Glu Met 260 265 270 Thr Ser Asp Thr Trp Leu Ser GlnGln Asn Glu Glu Pro Val Phe Ser 275 280 285 Arg Asp Gly Ser Lys Phe PheMet Thr Val Pro Val Lys Gln Gly Gly 290 295 300 Arg Gly Glu Phe His HisIle Ala Met Phe Leu Ile Gln Ser Lys Ser 305 310 315 320 Glu Gln Ile ThrVal Arg His Leu Thr Ser Gly Asn Trp Glu Val Ile 325 330 335 Lys Ile LeuAla Tyr Asp Glu Thr Thr Gln Lys Ile Tyr Phe Leu Ser 340 345 350 Thr GluSer Ser Pro Arg Gly Arg Gln Leu Tyr Ser Ala Ser Thr Glu 355 360 365 GlyLeu Leu Asn Arg Gln Cys Ile Ser Cys Asn Phe Met Lys Glu Gln 370 375 380Cys Thr Tyr Phe Asp Ala Ser Phe Ser Pro Met Asn Gln His Phe Leu 385 390395 400 Leu Phe Cys Glu Gly Pro Arg Val Pro Val Val Ser Leu His Ser Thr405 410 415 Asp Asn Pro Ala Lys Tyr Phe Ile Leu Glu Ser Asn Ser Met LeuLys 420 425 430 Glu Ala Ile Leu Lys Lys Lys Ile Gly Lys Pro Glu Ile LysIle Leu 435 440 445 His Ile Asp Asp Tyr Glu Leu Pro Leu Gln Leu Ser LeuPro Lys Asp 450 455 460 Phe Met Asp Arg Asn Gln Tyr Ala Leu Leu Leu IleMet Asp Glu Glu 465 470 475 480 Pro Gly Gly Gln Leu Val Thr Asp Lys PheHis Ile Asp Trp Asp Ser 485 490 495 Val Leu Ile Asp Met Asp Asn Val IleVal Ala Arg Phe Asp Gly Arg 500 505 510 Gly Ser Gly Phe Gln Gly Leu LysIle Leu Gln Glu Ile His Arg Arg 515 520 525 Leu Gly Ser Val Glu Val LysAsp Gln Ile Thr Ala Val Lys Phe Leu 530 535 540 Leu Lys Leu Pro Tyr IleAsp Ser Lys Arg Leu Ser Ile Phe Gly Lys 545 550 555 560 Gly Tyr Gly GlyTyr Ile Ala Ser Met Ile Leu Lys Ser Asp Glu Lys 565 570 575 Leu Phe LysCys Gly Ser Val Val Ala Pro Ile Thr Asp Leu Lys Leu 580 585 590 Tyr AlaSer Ala Phe Ser Glu Arg Tyr Leu Gly Met Pro Ser Lys Glu 595 600 605 GluSer Thr Tyr Gln Ala Ala Ser Val Leu His Asn Val His Gly Leu 610 615 620Lys Glu Glu Asn Ile Leu Ile Ile His Gly Thr Ala Asp Thr Lys Val 625 630635 640 His Phe Gln His Ser Ala Glu Leu Ile Lys His Leu Ile Lys Ala Gly645 650 655 Val Asn Tyr Thr Met Gln Val Tyr Pro Asp Glu Gly His Asn ValSer 660 665 670 Glu Lys Ser Lys Tyr His Leu Tyr Ser Thr Ile Leu Lys PhePhe Ser 675 680 685 Asp Cys Leu Lys Glu Glu Ile Ser Val Leu Pro Gln GluPro Glu Glu 690 695 700 Asp Glu 705 42 4541 DNA Homo sapiens 42gkctykgtkg wtsmagatac agatgtggtg tataaaagcg agaatggaca tgtcattaaa 60ctgaatatag aaacaaatgc taccacatta ttattggaaa acacaacttt tgtaaccttc 120aaagcatcaa gacattcagt ttcaccagat ttaaaatatg tccttctggc atatgatgtc 180aaacagattt ttcattattc gtatactgct tcatatgtga tttacaacat acacactagg 240gaagtttggg agttaaatcc tccagaagta gaggactccg tcttgcagta cgcggcctgg 300ggtgtccaag ggcagcagct gatttatatt tttgaaaata atatctacta tcaacctgat 360ataaagagca gttcattgcg actgacatct tctggaaaag aagaaataat ttttaatggg 420attgctgact ggttatatga agaggaactc ctgcattctc acatcgccca ctggtggtca 480ccagatggag aaagacttgc cttcctgatg ataaatgact ctttggtacc caccatggtt 540atccctcggt ttactggagc gttgtatccc aaaggaaagc agtatccgta tcctaaggca 600ggtcaagtga acccaacaat aaaattatat gttgtaaacc tgtatggacc aactcacact 660ttggagctca tgccacctga cagctttaaa tcaagagaat actatatcac tatggttaaa 720tgggtaagca ataccaagac tgtggtaaga tggttaaacc gacctcagaa catctccatc 780ctcacagtct gtgagaccac tacaggtgct tgtagtaaaa aatatgagat gacatcagat 840acgtggctct ctcagcagaa tgaggagccc gtgttttcta gagacggcag caaattcttt 900atgacagtgc ctgttaagca agggggacgt ggagaatttc accacatagc tatgttcctc 960atccagagta aaagtgagca aattaccgtg cggcatctga catcaggaaa ctgggaagtg 1020ataaagatct tggcatacga tgaaactact caaaaaattt actttctgag cactgaatct 1080tctcccagag gaaggcagct gtacagtgct tctactgaag gattattgaa tcgccaatgc 1140atttcatgta atttcatgaa agaacaatgt acatattttg atgccagttt tagtcccatg 1200aatcaacatt tcttattatt ctgtgaaggt ccaagggtcc cagtggtcag cctacatagt 1260acggacaacc cagcaaaata ttttatattg gaaagcaatt ctatgctgaa ggaagctatc 1320ctgaagaaga agataggaaa gccagaaatt aaaatccttc atattgacga ctatgaactt 1380cctttacagt tgtcccttcc caaagatttt atggaccgaa accagtatgc tcttctgtta 1440ataatggatg aagaaccagg aggccagctg gttacagata agttccatat tgactgggat 1500tccgtactca ttgacatgga taatgtcatt gtagcaagat ttgatggcag aggaagtgga 1560ttccagggtc tgaaaatttt gcaggagatt catcgaagat taggttcagt agaagtaaag 1620gaccaaataa cagctgtgaa atttttgctg aaactgcctt acattgactc caaaagatta 1680agcatttttg gaaagggtta tggtggctat attgcatcaa tgatcttaaa atcagatgaa 1740aagcttttta aatgtggatc cgtggttgca cctatcacag acttgaaatt gtatgcctca 1800gctttctctg aaagatacct tgggatgcca tctaaggaag aaagcactta ccaggcagcc 1860agtgtgctac ataatgttca tggcttgaaa gaagaaaata tattaataat tcatggaact 1920gctgacacaa aagttcattt ccaacactca gcagaattaa tcaagcacct aataaaagct 1980ggagtgaatt atactatgca ggtctaccca gatgaaggtc ataacgtatc tgagaagagc 2040aagtatcatc tctacagcac aatcctcaaa ttcttcagtg attgtttgaa ggaagaaata 2100tctgtgctac cacaggaacc agaagaagat gaataatgga ccgtatttat acagaactga 2160agggaatatt gaggctcaat gaaacctgac aaagagactg taatattgta gttgctccag 2220aatgtcaagg gcagcttacg gagatgtcac tggagcagca cgctcagaga cagtgaacta 2280gcatttgaat acacaagtcc aagtctactg tgttgctagg ggtgcagaac ccgtttcttt 2340gtatgagaga ggtcaaaggg ttggtttcct gggagaaatt agttttgcat taaagtagga 2400gtagtgcatg ttttcttctg ttatccccct gtttgttctg taactagttg ctctcatttt 2460aatttcactg gccaccatca tctttgcata taatgcacaa tctatcatct gtcctacagt 2520ccctgatctt tcatggctga gctgcaatct aacactttac tgtaccttta taataagtgc 2580aattctttca ttgtctatta ttatgcttaa gaaaatattc agttaataaa aaacagagta 2640ttttatgtaa tttctgtttt taaaaagaca ttattaaatg ggtcaaagga catatagaaa 2700tgtggatttc agcaccttcc aaagttcagc cagttatcag tagatacaat atctttaaat 2760gaacacacga gtgtatgtct cacaatatat atacacaagt gtgcatatac agttaatgaa 2820actatcttta aatgttattc atgctataaa gagtaaacgt ttgatgaatt agaagagatg 2880ctcttttcca agctataatg gatgctttgt ttaatgagcc aaatatgatg aaacattttt 2940tccaattcaa attctagcta ttgctttcct ataaatgttt gggttgtgtt tggtattgtt 3000tttagtggtt aatagttttc cagttgcatt taattttttg aatatgatac cttgtcacat 3060gtaaattaga tacttaaata ttaaattata gtttctgata aagaaatttt gttaacaatg 3120caatgccact gagtgctatt ttgctctttt ggtggagaag gcttttttca aaactcttgg 3180tccttttact tctttctctc agtgcagaat caattctcat tttcatcgta aaagcaaata 3240gctggattat ttcatttgcc agtttctatt tagtattcca tgcctgccca attcatctgt 3300tactgtttaa tttcaattct tctggtgaga attagaaatg aaatattttt tattcattgg 3360ccaaaaagtt cacagacagc agtgtttgct atttactttg aattgaaggc acaaaatgca 3420tcaattcctg tgctgtgttg acttgcagta gtaagtaact gagagcataa aataaacctg 3480actgtatgaa gtcaatttaa gtgatgagaa catttaactt tggtgactaa agtcagaata 3540tcttctcact tcacttaagg gatcttccag aagatatcta aaagtctgta ataagcttag 3600aagttcagat aaatctaggc aggatactgc atttttgtgg ttttaaaaaa gtccttagga 3660cagactgaat tatcataact tatggcatca ggaggaaact ttaaaatatc aaggaatcac 3720tcagtcaccc tcctgttttg ttgaaggatc aaccccaaat tctgggtatt tgagtacatg 3780tgaatcatgg atttggtatt caactttttc cctggatgct ttggaatcgt gtcttccatg 3840ctccactggg ttcaatttaa aataggagag gctttctctt ctgaaagatc cattttaggt 3900ctttttcaag aatagtgaac acatttttta acaaaataag ttgtaatttt aaaaggaaag 3960ttttgcctat tttattaaga tggaaatttc tttttaggct aatttgaaat ccaactgaag 4020ctttttaacc aatattttaa atttgaacca ctagagtttt ttatgatgca aatgattatg 4080ttgtctgaaa ggtgtggttt tattgaatgt ctatttgagt atcatttaaa aagtatttgc 4140cttttactgt catcatttct cttgttttat tattattatc aatgtttatc tatttttcaa 4200ttaatttaat acagtttcta atgtgaaaga catttttctg gaacccgttt tccccttaaa 4260cactaaagag acctcaagtg aaagcatatt gcttagtagg aaggtagaaa atgttaatcc 4320ctgcgattct ttgagtttta atgacagggt cattttcagt aaaggaaatg ctcaccaaca 4380catagtcacc aactattaaa ggaatcatgt gattggattt tcccctgtat acatgtaccc 4440ttggtcataa tcccactatt tcatacatat ttatgcattg ctagattttc ctaggactcc 4500aatagcatgc tttccaagtg ttattattcc cttaatgtta a 4541 43 691 PRT Homosapiens 43 Asp Thr Asp Val Val Tyr Lys Ser Glu Asn Gly His Val Ile LysLeu 1 5 10 15 Asn Ile Glu Thr Asn Ala Thr Thr Leu Leu Leu Glu Asn ThrThr Phe 20 25 30 Val Thr Phe Lys Ala Ser Arg His Ser Val Ser Pro Asp LeuLys Tyr 35 40 45 Val Leu Leu Ala Tyr Asp Val Lys Gln Ile Phe His Tyr SerTyr Thr 50 55 60 Ala Ser Tyr Val Ile Tyr Asn Ile His Thr Arg Glu Val TrpGlu Leu 65 70 75 80 Asn Pro Pro Glu Val Glu Asp Ser Val Leu Gln Tyr AlaAla Trp Gly 85 90 95 Val Gln Gly Gln Gln Leu Ile Tyr Ile Phe Glu Asn AsnIle Tyr Tyr 100 105 110 Gln Pro Asp Ile Lys Ser Ser Ser Leu Arg Leu ThrSer Ser Gly Lys 115 120 125 Glu Glu Ile Ile Phe Asn Gly Ile Ala Asp TrpLeu Tyr Glu Glu Glu 130 135 140 Leu Leu His Ser His Ile Ala His Trp TrpSer Pro Asp Gly Glu Arg 145 150 155 160 Leu Ala Phe Leu Met Ile Asn AspSer Leu Val Pro Thr Met Val Ile 165 170 175 Pro Arg Phe Thr Gly Ala LeuTyr Pro Lys Gly Lys Gln Tyr Pro Tyr 180 185 190 Pro Lys Ala Gly Gln ValAsn Pro Thr Ile Lys Leu Tyr Val Val Asn 195 200 205 Leu Tyr Gly Pro ThrHis Thr Leu Glu Leu Met Pro Pro Asp Ser Phe 210 215 220 Lys Ser Arg GluTyr Tyr Ile Thr Met Val Lys Trp Val Ser Asn Thr 225 230 235 240 Lys ThrVal Val Arg Trp Leu Asn Arg Pro Gln Asn Ile Ser Ile Leu 245 250 255 ThrVal Cys Glu Thr Thr Thr Gly Ala Cys Ser Lys Lys Tyr Glu Met 260 265 270Thr Ser Asp Thr Trp Leu Ser Gln Gln Asn Glu Glu Pro Val Phe Ser 275 280285 Arg Asp Gly Ser Lys Phe Phe Met Thr Val Pro Val Lys Gln Gly Gly 290295 300 Arg Gly Glu Phe His His Ile Ala Met Phe Leu Ile Gln Ser Lys Ser305 310 315 320 Glu Gln Ile Thr Val Arg His Leu Thr Ser Gly Asn Trp GluVal Ile 325 330 335 Lys Ile Leu Ala Tyr Asp Glu Thr Thr Gln Lys Ile SerAla Ser Thr 340 345 350 Glu Gly Leu Leu Asn Arg Gln Cys Ile Ser Cys AsnPhe Met Lys Glu 355 360 365 Gln Cys Thr Tyr Phe Asp Ala Ser Phe Ser ProMet Asn Gln His Phe 370 375 380 Leu Leu Phe Cys Glu Gly Pro Arg Val ProVal Val Ser Leu His Ser 385 390 395 400 Thr Asp Asn Pro Ala Lys Tyr PheIle Leu Glu Ser Asn Ser Met Leu 405 410 415 Lys Glu Ala Ile Leu Lys LysLys Ile Gly Lys Pro Glu Ile Lys Ile 420 425 430 Leu His Ile Asp Asp TyrGlu Leu Pro Leu Gln Leu Ser Leu Pro Lys 435 440 445 Asp Phe Met Asp ArgAsn Gln Tyr Ala Leu Leu Leu Ile Met Asp Glu 450 455 460 Glu Pro Gly GlyGln Leu Val Thr Asp Lys Phe His Ile Asp Trp Asp 465 470 475 480 Ser ValLeu Ile Asp Met Asp Asn Val Ile Val Ala Arg Phe Asp Gly 485 490 495 ArgGly Ser Gly Phe Gln Gly Leu Lys Ile Leu Gln Glu Ile His Arg 500 505 510Arg Leu Gly Ser Val Glu Val Lys Asp Gln Ile Thr Ala Val Lys Phe 515 520525 Leu Leu Lys Leu Pro Tyr Ile Asp Ser Lys Arg Leu Ser Ile Phe Gly 530535 540 Lys Gly Tyr Gly Gly Tyr Ile Ala Ser Met Ile Leu Lys Ser Asp Glu545 550 555 560 Lys Leu Phe Lys Cys Gly Ser Val Val Ala Pro Ile Thr AspLeu Lys 565 570 575 Leu Tyr Ala Ser Ala Phe Ser Glu Arg Tyr Leu Gly MetPro Ser Lys 580 585 590 Glu Glu Ser Thr Tyr Gln Ala Ala Ser Val Leu HisAsn Val His Gly 595 600 605 Leu Lys Glu Glu Asn Ile Leu Ile Ile His GlyThr Ala Asp Thr Lys 610 615 620 Val His Phe Gln His Ser Ala Glu Leu IleLys His Leu Ile Lys Ala 625 630 635 640 Gly Val Asn Tyr Thr Met Gln ValTyr Pro Asp Glu Gly His Asn Val 645 650 655 Ser Glu Lys Ser Lys Tyr HisLeu Tyr Ser Thr Ile Leu Lys Phe Phe 660 665 670 Ser Asp Cys Leu Lys GluGlu Ile Ser Val Leu Pro Gln Glu Pro Glu 675 680 685 Glu Asp Glu 690 444496 DNA Homo sapiens 44 gkctykgtkg wtsmagatac agatgtggtg tataaaagcgagaatggaca tgtcattaaa 60 ctgaatatag aaacaaatgc taccacatta ttattggaaaacacaacttt tgtaaccttc 120 aaagcatcaa gacattcagt ttcaccagat ttaaaatatgtccttctggc atatgatgtc 180 aaacagattt ttcattattc gtatactgct tcatatgtgatttacaacat acacactagg 240 gaagtttggg agttaaatcc tccagaagta gaggactccgtcttgcagta cgcggcctgg 300 ggtgtccaag ggcagcagct gatttatatt tttgaaaataatatctacta tcaacctgat 360 ataaagagca gttcattgcg actgacatct tctggaaaagaagaaataat ttttaatggg 420 attgctgact ggttatatga agaggaactc ctgcattctcacatcgccca ctggtggtca 480 ccagatggag aaagacttgc cttcctgatg ataaatgactctttggtacc caccatggtt 540 atccctcggt ttactggagc gttgtatccc aaaggaaagcagtatccgta tcctaaggca 600 ggtcaagtga acccaacaat aaaattatat gttgtaaacctgtatggacc aactcacact 660 ttggagctca tgccacctga cagctttaaa tcaagagaatactatatcac tatggttaaa 720 tgggtaagca ataccaagac tgtggtaaga tggttaaaccgacctcagaa catctccatc 780 ctcacagtct gtgagaccac tacaggtgct tgtagtaaaaaatatgagat gacatcagat 840 acgtggctct ctcagcagaa tgaggagccc gtgttttctagagacggcag caaattcttt 900 atgacagtgc ctgttaagca agggggacgt ggagaatttcaccacatagc tatgttcctc 960 atccagagta aaagtgagca aattaccgtg cggcatctgacatcaggaaa ctgggaagtg 1020 ataaagatct tggcatacga tgaaactact caaaaaatcagtgcttctac tgaaggatta 1080 ttgaatcgcc aatgcatttc atgtaatttc atgaaagaacaatgtacata ttttgatgcc 1140 agttttagtc ccatgaatca acatttctta ttattctgtgaaggtccaag ggtcccagtg 1200 gtcagcctac atagtacgga caacccagca aaatattttatattggaaag caattctatg 1260 ctgaaggaag ctatcctgaa gaagaagata ggaaagccagaaattaaaat ccttcatatt 1320 gacgactatg aacttccttt acagttgtcc cttcccaaagattttatgga ccgaaaccag 1380 tatgctcttc tgttaataat ggatgaagaa ccaggaggccagctggttac agataagttc 1440 catattgact gggattccgt actcattgac atggataatgtcattgtagc aagatttgat 1500 ggcagaggaa gtggattcca gggtctgaaa attttgcaggagattcatcg aagattaggt 1560 tcagtagaag taaaggacca aataacagct gtgaaatttttgctgaaact gccttacatt 1620 gactccaaaa gattaagcat ttttggaaag ggttatggtggctatattgc atcaatgatc 1680 ttaaaatcag atgaaaagct ttttaaatgt ggatccgtggttgcacctat cacagacttg 1740 aaattgtatg cctcagcttt ctctgaaaga taccttgggatgccatctaa ggaagaaagc 1800 acttaccagg cagccagtgt gctacataat gttcatggcttgaaagaaga aaatatatta 1860 ataattcatg gaactgctga cacaaaagtt catttccaacactcagcaga attaatcaag 1920 cacctaataa aagctggagt gaattatact atgcaggtctacccagatga aggtcataac 1980 gtatctgaga agagcaagta tcatctctac agcacaatcctcaaattctt cagtgattgt 2040 ttgaaggaag aaatatctgt gctaccacag gaaccagaagaagatgaata atggaccgta 2100 tttatacaga actgaaggga atattgaggc tcaatgaaacctgacaaaga gactgtaata 2160 ttgtagttgc tccagaatgt caagggcagc ttacggagatgtcactggag cagcacgctc 2220 agagacagtg aactagcatt tgaatacaca agtccaagtctactgtgttg ctaggggtgc 2280 agaacccgtt tctttgtatg agagaggtca aagggttggtttcctgggag aaattagttt 2340 tgcattaaag taggagtagt gcatgttttc ttctgttatccccctgtttg ttctgtaact 2400 agttgctctc attttaattt cactggccac catcatctttgcatataatg cacaatctat 2460 catctgtcct acagtccctg atctttcatg gctgagctgcaatctaacac tttactgtac 2520 ctttataata agtgcaattc tttcattgtc tattattatgcttaagaaaa tattcagtta 2580 ataaaaaaca gagtatttta tgtaatttct gtttttaaaaagacattatt aaatgggtca 2640 aaggacatat agaaatgtgg atttcagcac cttccaaagttcagccagtt atcagtagat 2700 acaatatctt taaatgaaca cacgagtgta tgtctcacaatatatataca caagtgtgca 2760 tatacagtta atgaaactat ctttaaatgt tattcatgctataaagagta aacgtttgat 2820 gaattagaag agatgctctt ttccaagcta taatggatgctttgtttaat gagccaaata 2880 tgatgaaaca ttttttccaa ttcaaattct agctattgctttcctataaa tgtttgggtt 2940 gtgtttggta ttgtttttag tggttaatag ttttccagttgcatttaatt ttttgaatat 3000 gataccttgt cacatgtaaa ttagatactt aaatattaaattatagtttc tgataaagaa 3060 attttgttaa caatgcaatg ccactgagtg ctattttgctcttttggtgg agaaggcttt 3120 tttcaaaact cttggtcctt ttacttcttt ctctcagtgcagaatcaatt ctcattttca 3180 tcgtaaaagc aaatagctgg attatttcat ttgccagtttctatttagta ttccatgcct 3240 gcccaattca tctgttactg tttaatttca attcttctggtgagaattag aaatgaaata 3300 ttttttattc attggccaaa aagttcacag acagcagtgtttgctattta ctttgaattg 3360 aaggcacaaa atgcatcaat tcctgtgctg tgttgacttgcagtagtaag taactgagag 3420 cataaaataa acctgactgt atgaagtcaa tttaagtgatgagaacattt aactttggtg 3480 actaaagtca gaatatcttc tcacttcact taagggatcttccagaagat atctaaaagt 3540 ctgtaataag cttagaagtt cagataaatc taggcaggatactgcatttt tgtggtttta 3600 aaaaagtcct taggacagac tgaattatca taacttatggcatcaggagg aaactttaaa 3660 atatcaagga atcactcagt caccctcctg ttttgttgaaggatcaaccc caaattctgg 3720 gtatttgagt acatgtgaat catggatttg gtattcaactttttccctgg atgctttgga 3780 atcgtgtctt ccatgctcca ctgggttcaa tttaaaataggagaggcttt ctcttctgaa 3840 agatccattt taggtctttt tcaagaatag tgaacacattttttaacaaa ataagttgta 3900 attttaaaag gaaagttttg cctattttat taagatggaaatttcttttt aggctaattt 3960 gaaatccaac tgaagctttt taaccaatat tttaaatttgaaccactaga gttttttatg 4020 atgcaaatga ttatgttgtc tgaaaggtgt ggttttattgaatgtctatt tgagtatcat 4080 ttaaaaagta tttgcctttt actgtcatca tttctcttgttttattatta ttatcaatgt 4140 ttatctattt ttcaattaat ttaatacagt ttctaatgtgaaagacattt ttctggaacc 4200 cgttttcccc ttaaacacta aagagacctc aagtgaaagcatattgctta gtaggaaggt 4260 agaaaatgtt aatccctgcg attctttgag ttttaatgacagggtcattt tcagtaaagg 4320 aaatgctcac caacacatag tcaccaacta ttaaaggaatcatgtgattg gattttcccc 4380 tgtatacatg tacccttggt cataatccca ctatttcatacatatttatg cattgctaga 4440 ttttcctagg actccaatag catgctttcc aagtgttattattcccttaa tgttaa 4496 45 29 DNA Homo sapiens 45 cggtaccatg gcagcagcaatggaaacag 29 46 39 DNA Homo sapiens 46 ggagctcgcg gccgctcata tcacttttagagcagcaat 39 47 27 DNA Homo sapiens 47 caagctttat cacttttaga gcagcaa 2748 22 DNA Homo sapiens 48 cacattcttg ctgcatcagt ca 22 49 22 DNA Homosapiens 49 ttgggtcatc ttcaggactt ga 22 50 27 DNA Homo sapiens 50caagcttacc atggccacca ccgggac 27 51 37 DNA Homo sapiens 51 cggatccgcggccgctcaga ggtattcctg tagaaag 37 52 27 DNA Homo sapiens 52 cggatccaggtattcctgta gaaagtg 27 53 20 DNA Homo sapiens 53 tacgccgtgg ttgtgattga 2054 20 DNA Homo sapiens 54 ccatacttct cggccacgaa 20 55 19 DNA Homosapiens 55 gcctgggatt gtgcactgt 19 56 29 DNA Homo sapiens 56 gtgtattcaaatgctagttc actgtctct 29 57 22 DNA Homo sapiens 57 agctagcact gtccagggtcct 22 58 25 DNA Homo sapiens 58 agggcccttc atcttcttct ggttc 25 59 19 PRTHomo sapiens 59 Val Glu Asp Asp Val Met Glu Arg Gln Arg Leu Ile Glu SerVal Pro 1 5 10 15 Asp Ser Val 60 19 PRT Homo sapiens 60 Ser Thr Glu AsnGlu Glu Gln Arg Leu Ala Ser Ala Arg Ala Val Pro 1 5 10 15 Arg Asn Val 6115 PRT Homo sapiens 61 Lys Glu Ala Ile Leu Lys Lys Lys Ile Gly Lys ProGlu Ile Lys 1 5 10 15

What is claimed is:
 1. Isolated nucleic acid which encodes (a) apolypeptide, which includes the amino acid sequence of one of SEQ IDNOS: 1, 3 and 5, or (b) a polypeptide having an amino acid sequence thatis at least about 70% similar thereto and exhibits the same biologicalfunction; or which is an alternative splice variant of one of SEQ IDNOS: 2, 4 and 6; or which is a probe comprising at least 14 contiguousnucleotides from said nucleic acid encoding (a) or (b); or which iscomplementary to any one of the foregoing.
 2. The isolated nucleic acidof claim 1 which is DNA or RNA.
 3. The isolated nucleic acid of claim 1which is a DNA transcript that includes the entire length of any one ofSEQ ID NOS: 2, 4 and 6 or which is complementary to the entire codingregion of one of SEQ ID NOS: 2, 4 and
 6. 4. An antisense oligonucleotidedirected against the DNA of claim
 3. 5. The isolated nucleic acid ofclaim 1 which is an RNA transcript which includes the entire length ofany one of SEQ ID NOS: 2, 4 and
 6. 6. The isolated nucleic acid of claim1 which is an alternative splice variant of one of SEQ ID NOS: 2, 4 and6.
 7. A polypeptide encoded by the nucleic acid of claim
 6. 8. A nucleicacid probe according to claim 1 comprising at least 14 contiguousnucleotides from one of SEQ ID NOS: 2, 4 and
 6. 9. An isolatedrecombinant polynucleotide molecule comprising nucleic acid according toclaim 1 plus expression-controlling elements linked operably with saidnucleic acid to drive expression thereof.
 10. An expression vectorcomprising the nucleic acid of claim I encoding a polypeptide having theentire amino acid sequence set forth in any one of SEQ ID NOS: 1, 3 and5 operably linked to a promoter, said expression vector being present ina compatible host cell.
 11. A mammalian, insect or bacterial host cellthat has been genetically engineered by the insertion of nucleic acidaccording to claim 1 which codes for at least the mature protein portionof the amino acid sequence of SEQ ID NO: 1, 3 or
 5. 12. A process forproducing a polypeptide which includes the mature protein portion of oneof SEQ ID NOS: 1, 3 and 5, which process comprises culturing the hostcell of claim 11 under conditions sufficient for the production of saidpolypeptide.
 13. The process of claim 12 wherein said polypeptide isexpressed at the surface of said cell and further includes the step ofrecovering the polypeptide or a fragment thereof from the culture.
 14. Apolypeptide which may be optionally glycosylated, and which (a) has theamino acid sequence of a mature protein set forth in any one of SEQ IDNOS: 1, 3 and 5, (b) has the amino acid sequence of a mature proteinhaving at least about 70% similarity to one of the mature proteins of(a) and which exhibits the same biological function, or (c) is animmunologically reactive fragment of (a).
 15. The polypeptide accordingto claim 14 which is a mature protein having at least about 95%similarity to (a).
 16. The polypeptide according to claim 14 havingeither the amino acid sequence of the mature protein of one of SEQ IDNOS: 1, 3 and 5 or of a fragment thereof which exhibits the samebiological function as the respective mature protein.
 17. A DPRPantagonist which inhibits the biological function of one of said matureproteins of claim
 14. 18. An antibody that recognizes a polypeptide or afragment according to claim
 14. 19. The antibody of claim 18 whichrecognizes a polypeptide having an amino acid sequence of SEQ ID NO: 1or 3 or
 5. 20. A method for the screening for a compound capable ofinhibiting the enzymatic activity of at least one mature protein ofclaim 14, which method comprises incubating said mature protein and asuitable substrate for said mature protein in the presence of one ormore test compounds or salts thereof, measuring the enzymatic activityof said mature protein, comparing said activity with comparable activitydetermined in the absence of a test compound, and selecting the testcompound or compounds that reduce the enzymatic activity.
 21. A methodfor the screening for a compound capable of inhibiting the enzymaticactivity of DPPIV that does not inhibit the enzymatic activity of atleast one of the polypeptides of claim 16, which method comprisesincubating said polypeptide and a suitable substrate for saidpolypeptide in the presence of one or more inhibitors of DPPIV or saltsthereof, measuring the enzymatic activity of said polypeptide, comparingsaid activity with comparable activity determined in the absence of theDPPIV inhibitor, and selecting a compound that does not reduce theenzymatic activity of said polypeptide.